Francesco Cucca
Outgoing Director
H-index – July 2019 – :64 (Scopus) 71 (Google scholar)
Education:
| 1977 – 1984 | University of Cagliari Medical School, Italy: degree of M.D. with honours |
| 1985 – 1989 | Specialization in Paediatrics, University of Cagliari, with honours |
Current position:
| 2011 – present | Full Professor of Medical Genetics, University of Sassari, Italy |
Previous positions:
| 2009 – June 2019 | Director of the Institute for Research in Genetics and Biomedicine (IRGB), of the National Research Council (CNR), Italy |
| 2005 – 2010 | Associate Professor of Medical Genetics, University of Sassari, Italy |
| 1998 – 2004 | Assistant Professor in Pediatrics, Department of Biomedical Science and Biotechnology, University of Cagliari, Italy |
| 1991 – 1993 | Attending Pediatrician, Pediatrics Unit, Brotzu Hospital, Cagliari, Italy |
Fellowships:
| 1994 – 1997 | Postdoctoral fellow at the Nuffield Department of Surgery, Wellcome Trust Centre for Human Genetics, University of Oxford, UK, in the Laboratory of John A. Todd |
Institutional responsibilities:
- During the last 15 years I have served as reviewer for various scientific journals like Diabetes, Lancet Neurology, European Journal of Human Genetics, Human Molecular Genetics, American Journal of Human Genetics and Nature Genetics where, because of time constraints, I have concentrated most of my reviewer activity in the last few years.
- I have been a member of the steering committee of the FISM (Italian Multiple Sclerosis Foundation) for many years (from 2010 to 2013).
Major collaborations:
A strategic asset for increasing the critical mass and improving the quality of our research activities in Sardinia have been international collaborations I have set up with leading scientists in the fields of functional genetics. To name the main ones:
- David Schlessinger, Distinguished Researcher NIH/NIA, National Institute on Aging, Baltimore, USA; as the contract officer of our NIA intramural grant and my co-PI of the SardiNIA project.
- Goncalo Abecasis, Head Department of Biostatistics, University of Michigan, AnnArbor; key partner over the last ~10 years on the genetic analyses performed in the SardiNIA project
- John Todd, Professor of Precision Medicine; Oxford University (UK); my mentor in the initial work on autoimmunity more than 20 years ago and still an important collaborator in the current research activities.
- John Novembre, Associate Professor Human Genetics, University of Chicago; relevant collaborator on work on population genetics and ancient DNA analysis.
- Stephen Montgomery, Director of Genome Informatics, Department of Pathology, Stanford University, USA; a critical collaborator in developing new tools for analysis of RNA seq data.
On-going Grants of which I am the principal investigator/coordinator:
| Project Title | Funding source | Amount | Period |
|---|---|---|---|
| Progenia/SardiNIA: Longitudinal studies for Age Associated Conditions in a Sardinia Population Cohort | National Institute of Health (USA) | $ 4.345.690 | 2016-2021 |
| Elucidation of BAFF role in Multiple Sclerosis onset. | Fondazione Italiana Sclerosi Multipla (FISM) | € 240.000 | 2015-2019 |
| ImmunoAgeing – An integrated approach to dissect determinants, risk factors and pathways of ageing of the immune system | EU H2020 | €. 5,850,000.00 (of which € 2.514.063 for the IRGB unit) |
2015-2019 |
| NEOGENIA – A pilot study of neonatal genetic screening in the Ogliastra population | Sardegna Ricerche | € 360.000 | 2013-2018 |
| Ageing: molecular innovations for heath improvement of the elderly. | National Research Council Italy | € 1.339.000 | 2011-2018 |
Most significant publications:
My research activity includes 206 peer reviewed work (see https://orcid.org/0000-0002-7414-1995) with a total H-index (Scopus) of 64 (July 2019). Below are reported my 10 more significant publications in the last 5 years, and my 20 more significant publications in the previous years
Floris, M; Olla, S; Schlessinger, D; Cucca, F Genetic-Driven Druggable Target Identification and Validation Journal Article Trends Genet., 34 (7), pp. 558–570, 2018. @article{pmid29803319, title = {Genetic-Driven Druggable Target Identification and Validation}, author = {M Floris and S Olla and D Schlessinger and F Cucca}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29803319}, year = {2018}, date = {2018-07-01}, journal = {Trends Genet.}, volume = {34}, number = {7}, pages = {558--570}, abstract = {Choosing the right biological target is the critical primary decision for the development of new drugs. Systematic genetic association testing of both human diseases and quantitative traits, along with resultant findings of coincident associations between them, is becoming a powerful approach to infer drug targetable candidates and generate in vitro tests to identify compounds that can modulate them therapeutically. Here, we discuss opportunities and challenges, and infer criteria for the optimal use of genetic findings in the drug discovery pipeline.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Choosing the right biological target is the critical primary decision for the development of new drugs. Systematic genetic association testing of both human diseases and quantitative traits, along with resultant findings of coincident associations between them, is becoming a powerful approach to infer drug targetable candidates and generate in vitro tests to identify compounds that can modulate them therapeutically. Here, we discuss opportunities and challenges, and infer criteria for the optimal use of genetic findings in the drug discovery pipeline. |
Chiang, C W K; Marcus, J H; Sidore, C; Biddanda, A; Al-Asadi, H; Zoledziewska, M; Pitzalis, M; Busonero, F; Maschio, A; Pistis, G; Steri, M; Angius, A; Lohmueller, K E; Abecasis, G R; Schlessinger, D; Cucca, F; Novembre, J Genomic history of the Sardinian population Journal Article Nat. Genet., 50 (10), pp. 1426–1434, 2018. @article{pmid30224645, title = {Genomic history of the Sardinian population}, author = {C W K Chiang and J H Marcus and C Sidore and A Biddanda and H Al-Asadi and M Zoledziewska and M Pitzalis and F Busonero and A Maschio and G Pistis and M Steri and A Angius and K E Lohmueller and G R Abecasis and D Schlessinger and F Cucca and J Novembre}, url = {https://www.nature.com/articles/s41588-018-0215-8}, year = {2018}, date = {2018-01-01}, journal = {Nat. Genet.}, volume = {50}, number = {10}, pages = {1426--1434}, abstract = {The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations. |
Olivieri, Anna; Sidore, Carlo; Achilli, Alessandro; Angius, Andrea; Posth, Cosimo; ä, Anja Furtw; Brandini, Stefania; Capodiferro, Marco Rosario; Gandini, Francesca; Zoledziewska, Magdalena; Pitzalis, Maristella; Maschio, Andrea; Busonero, Fabio; Lai, Luca; Skeates, Robin; Gradoli, Maria Giuseppina; Beckett, Jessica; Marongiu, Michele; Mazzarello, Vittorio; Marongiu, Patrizia; Rubino, Salvatore; Rito, Teresa; Macaulay, Vincent; Semino, Ornella; Pala, Maria; ç, Gon; Schlessinger, David; Conde-Sousa, Eduardo; Soares, Pedro; Richards, Martin B; Cucca, Francesco; Torroni, Antonio Mitogenome Diversity in Sardinians: A Genetic Window onto an Island's Past Journal Article Molecular Biology and Evolution, 34 (5), pp. 1230–1239, 2017, ISSN: 1537-1719. @article{olivieri_mitogenome_2017, title = {Mitogenome Diversity in Sardinians: A Genetic Window onto an Island's Past}, author = {Anna Olivieri and Carlo Sidore and Alessandro Achilli and Andrea Angius and Cosimo Posth and Anja Furtw{ä}ngler and Stefania Brandini and Marco Rosario Capodiferro and Francesca Gandini and Magdalena Zoledziewska and Maristella Pitzalis and Andrea Maschio and Fabio Busonero and Luca Lai and Robin Skeates and Maria Giuseppina Gradoli and Jessica Beckett and Michele Marongiu and Vittorio Mazzarello and Patrizia Marongiu and Salvatore Rubino and Teresa Rito and Vincent Macaulay and Ornella Semino and Maria Pala and Gon{ç}alo R Abecasis and David Schlessinger and Eduardo Conde-Sousa and Pedro Soares and Martin B Richards and Francesco Cucca and Antonio Torroni}, doi = {10.1093/molbev/msx082}, issn = {1537-1719}, year = {2017}, date = {2017-05-01}, journal = {Molecular Biology and Evolution}, volume = {34}, number = {5}, pages = {1230--1239}, abstract = {Sardinians are öutliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Sardinians are öutliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia. |
Pala, Mauro; Zappala, Zachary; Marongiu, Mara; Li, Xin; Davis, Joe R; Cusano, Roberto; Crobu, Francesca; Kukurba, Kimberly R; Gloudemans, Michael J; Reinier, Frederic; Berutti, Riccardo; Piras, Maria G; Mulas, Antonella; Zoledziewska, Magdalena; Marongiu, Michele; Sorokin, Elena P; Hess, Gaelen T; Smith, Kevin S; Busonero, Fabio; Maschio, Andrea; Steri, Maristella; Sidore, Carlo; Sanna, Serena; Fiorillo, Edoardo; Bassik, Michael C; Sawcer, Stephen J; Battle, Alexis; Novembre, John; Jones, Chris; Angius, Andrea; ç, Gon; Schlessinger, David; Cucca, Francesco; Montgomery, Stephen B Population- and individual-specific regulatory variation in Sardinia Journal Article Nature Genetics, 49 (5), pp. 700–707, 2017, ISSN: 1546-1718. @article{pala_population-_2017, title = {Population- and individual-specific regulatory variation in Sardinia}, author = {Mauro Pala and Zachary Zappala and Mara Marongiu and Xin Li and Joe R Davis and Roberto Cusano and Francesca Crobu and Kimberly R Kukurba and Michael J Gloudemans and Frederic Reinier and Riccardo Berutti and Maria G Piras and Antonella Mulas and Magdalena Zoledziewska and Michele Marongiu and Elena P Sorokin and Gaelen T Hess and Kevin S Smith and Fabio Busonero and Andrea Maschio and Maristella Steri and Carlo Sidore and Serena Sanna and Edoardo Fiorillo and Michael C Bassik and Stephen J Sawcer and Alexis Battle and John Novembre and Chris Jones and Andrea Angius and Gon{ç}alo R Abecasis and David Schlessinger and Francesco Cucca and Stephen B Montgomery}, doi = {10.1038/ng.3840}, issn = {1546-1718}, year = {2017}, date = {2017-05-01}, journal = {Nature Genetics}, volume = {49}, number = {5}, pages = {700--707}, abstract = {Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk. |
Steri, Maristella; Orrù, Valeria; Idda, Laura M; Pitzalis, Maristella; Pala, Mauro; Zara, Ilenia; Sidore, Carlo; Faà, Valeria; Floris, Matteo; Deiana, Manila; Asunis, Isadora; Porcu, Eleonora; Mulas, Antonella; Piras, Maria G; Lobina, Monia; Lai, Sandra; Marongiu, Mara; Serra, Valentina; Marongiu, Michele; Sole, Gabriella; Busonero, Fabio; Maschio, Andrea; Cusano, Roberto; Cuccuru, Gianmauro; Deidda, Francesca; Poddie, Fausto; Farina, Gabriele; Dei, Mariano; Virdis, Francesca; Olla, Stefania; Satta, Maria A; Pani, Mario; Delitala, Alessandro; Cocco, Eleonora; Frau, Jessica; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Ferrigno, Paola; Ban, Maria; Barizzone, Nadia; Leone, Maurizio; Guerini, Franca R; Piga, Matteo; Firinu, Davide; Kockum, Ingrid; Lima Bomfim, Izaura ; Olsson, Tomas; Alfredsson, Lars; Suarez, Ana; Carreira, Patricia E; Castillo-Palma, Maria J; Marcus, Joseph H; Congia, Mauro; Angius, Andrea; Melis, Maurizio; Gonzalez, Antonio; ó}n Riquelme, Marta {Alarc E; da Silva, Berta M; Marchini, Maurizio; Danieli, Maria G; Del Giacco, Stefano ; Mathieu, Alessandro; Pani, Antonello; Montgomery, Stephen B; Rosati, Giulio; Hillert, Jan; Sawcer, Stephen; D'Alfonso, Sandra; Todd, John A; Novembre, John; ç, Gon; Whalen, Michael B; Marrosu, Maria G; Meloni, Alessandra; Sanna, Serena; Gorospe, Myriam; Schlessinger, David; Fiorillo, Edoardo; Zoledziewska, Magdalena; Cucca, Francesco Overexpression of the Cytokine BAFF and Autoimmunity Risk Journal Article The New England Journal of Medicine, 376 (17), pp. 1615–1626, 2017, ISSN: 1533-4406, (See Editorials, Korn T, Oukka M. A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis. N Engl J Med. 2017 Apr 27;376(17):1680-1681. doi: 10.1056/NEJMe1700720.; Stohl W., Systemic lupus erythematosus: BAFF emerges from the genetic shadows. Nat Rev Rheumatol. 2017 Jun 15. doi: 10.1038/nrrheum.2017.99; Comabella M. Neuroimmunology: B cells and variant BAFF in autoimmune disease. Nat Rev Neurol. 2017 Jun 16. doi: 10.1038/nrneurol.2017.87.). @article{steri_overexpression_2017, title = {Overexpression of the Cytokine BAFF and Autoimmunity Risk}, author = {Maristella Steri and Valeria Orrù and Laura M Idda and Maristella Pitzalis and Mauro Pala and Ilenia Zara and Carlo Sidore and Valeria Faà and Matteo Floris and Manila Deiana and Isadora Asunis and Eleonora Porcu and Antonella Mulas and Maria G Piras and Monia Lobina and Sandra Lai and Mara Marongiu and Valentina Serra and Michele Marongiu and Gabriella Sole and Fabio Busonero and Andrea Maschio and Roberto Cusano and Gianmauro Cuccuru and Francesca Deidda and Fausto Poddie and Gabriele Farina and Mariano Dei and Francesca Virdis and Stefania Olla and Maria A Satta and Mario Pani and Alessandro Delitala and Eleonora Cocco and Jessica Frau and Giancarlo Coghe and Lorena Lorefice and Giuseppe Fenu and Paola Ferrigno and Maria Ban and Nadia Barizzone and Maurizio Leone and Franca R Guerini and Matteo Piga and Davide Firinu and Ingrid Kockum and Izaura {Lima Bomfim} and Tomas Olsson and Lars Alfredsson and Ana Suarez and Patricia E Carreira and Maria J Castillo-Palma and Joseph H Marcus and Mauro Congia and Andrea Angius and Maurizio Melis and Antonio Gonzalez and Marta E {Alarc{ó}n Riquelme} and Berta M da Silva and Maurizio Marchini and Maria G Danieli and Stefano {Del Giacco} and Alessandro Mathieu and Antonello Pani and Stephen B Montgomery and Giulio Rosati and Jan Hillert and Stephen Sawcer and Sandra D'Alfonso and John A Todd and John Novembre and Gon{ç}alo R Abecasis and Michael B Whalen and Maria G Marrosu and Alessandra Meloni and Serena Sanna and Myriam Gorospe and David Schlessinger and Edoardo Fiorillo and Magdalena Zoledziewska and Francesco Cucca}, doi = {10.1056/NEJMoa1610528}, issn = {1533-4406}, year = {2017}, date = {2017-01-01}, journal = {The New England Journal of Medicine}, volume = {376}, number = {17}, pages = {1615--1626}, abstract = {BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).}, note = {See Editorials, Korn T, Oukka M. A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis. N Engl J Med. 2017 Apr 27;376(17):1680-1681. doi: 10.1056/NEJMe1700720.; Stohl W., Systemic lupus erythematosus: BAFF emerges from the genetic shadows. Nat Rev Rheumatol. 2017 Jun 15. doi: 10.1038/nrrheum.2017.99; Comabella M. Neuroimmunology: B cells and variant BAFF in autoimmune disease. Nat Rev Neurol. 2017 Jun 16. doi: 10.1038/nrneurol.2017.87.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.). |
Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Porcu, Eleonora; Naitza, Silvia; Zoledziewska, Magdalena; Mulas, Antonella; Pistis, Giorgio; Steri, Maristella; Danjou, Fabrice; Kwong, Alan; Ortega Del Vecchyo, Vicente Diego ; Chiang, Charleston W K; Bragg-Gresham, Jennifer; Pitzalis, Maristella; Nagaraja, Ramaiah; Tarrier, Brendan; Brennan, Christine; Uzzau, Sergio; Fuchsberger, Christian; Atzeni, Rossano; Reinier, Frederic; Berutti, Riccardo; Huang, Jie; Timpson, Nicholas J; Toniolo, Daniela; Gasparini, Paolo; Malerba, Giovanni; Dedoussis, George; Zeggini, Eleftheria; Soranzo, Nicole; Jones, Chris; Lyons, Robert; Angius, Andrea; Kang, Hyun M; Novembre, John; Sanna, Serena; Schlessinger, David; Cucca, Francesco; ç, Gon Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers Journal Article Nature Genetics, 47 (11), pp. 1272–1281, 2015, ISSN: 1546-1718. @article{sidore_genome_2015, title = {Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers}, author = {Carlo Sidore and Fabio Busonero and Andrea Maschio and Eleonora Porcu and Silvia Naitza and Magdalena Zoledziewska and Antonella Mulas and Giorgio Pistis and Maristella Steri and Fabrice Danjou and Alan Kwong and Vicente Diego {Ortega Del Vecchyo} and Charleston W K Chiang and Jennifer Bragg-Gresham and Maristella Pitzalis and Ramaiah Nagaraja and Brendan Tarrier and Christine Brennan and Sergio Uzzau and Christian Fuchsberger and Rossano Atzeni and Frederic Reinier and Riccardo Berutti and Jie Huang and Nicholas J Timpson and Daniela Toniolo and Paolo Gasparini and Giovanni Malerba and George Dedoussis and Eleftheria Zeggini and Nicole Soranzo and Chris Jones and Robert Lyons and Andrea Angius and Hyun M Kang and John Novembre and Serena Sanna and David Schlessinger and Francesco Cucca and Gon{ç}alo R Abecasis}, doi = {10.1038/ng.3368}, issn = {1546-1718}, year = {2015}, date = {2015-11-01}, journal = {Nature Genetics}, volume = {47}, number = {11}, pages = {1272--1281}, abstract = {We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population. |
Danjou, Fabrice; Zoledziewska, Magdalena; Sidore, Carlo; Steri, Maristella; Busonero, Fabio; Maschio, Andrea; Mulas, Antonella; Perseu, Lucia; Barella, Susanna; Porcu, Eleonora; Pistis, Giorgio; Pitzalis, Maristella; Pala, Mauro; Menzel, Stephan; Metrustry, Sarah; Spector, Timothy D; Leoni, Lidia; Angius, Andrea; Uda, Manuela; Moi, Paolo; Thein, Swee Lay; Galanello, Renzo; ç, Gon; Schlessinger, David; Sanna, Serena; Cucca, Francesco Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels Journal Article Nature Genetics, 47 (11), pp. 1264–1271, 2015, ISSN: 1546-1718. @article{danjou_genome-wide_2015, title = {Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels}, author = {Fabrice Danjou and Magdalena Zoledziewska and Carlo Sidore and Maristella Steri and Fabio Busonero and Andrea Maschio and Antonella Mulas and Lucia Perseu and Susanna Barella and Eleonora Porcu and Giorgio Pistis and Maristella Pitzalis and Mauro Pala and Stephan Menzel and Sarah Metrustry and Timothy D Spector and Lidia Leoni and Andrea Angius and Manuela Uda and Paolo Moi and Swee Lay Thein and Renzo Galanello and Gon{ç}alo R Abecasis and David Schlessinger and Serena Sanna and Francesco Cucca}, doi = {10.1038/ng.3307}, issn = {1546-1718}, year = {2015}, date = {2015-11-01}, journal = {Nature Genetics}, volume = {47}, number = {11}, pages = {1264--1271}, abstract = {We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production. |
Zoledziewska, Magdalena; Sidore, Carlo; Chiang, Charleston W K; Sanna, Serena; Mulas, Antonella; Steri, Maristella; Busonero, Fabio; Marcus, Joseph H; Marongiu, Michele; Maschio, Andrea; Del Vecchyo, Diego Ortega ; Floris, Matteo; Meloni, Antonella; Delitala, Alessandro; Concas, Maria Pina; Murgia, Federico; Biino, Ginevra; Vaccargiu, Simona; Nagaraja, Ramaiah; Lohmueller, Kirk E; Consortium, UK10K; Timpson, Nicholas J; Soranzo, Nicole; Tachmazidou, Ioanna; Dedoussis, George; Zeggini, Eleftheria; Group, Understanding Society Scientific; Uzzau, Sergio; Jones, Chris; Lyons, Robert; Angius, Andrea; ç, Gon; Novembre, John; Schlessinger, David; Cucca, Francesco Height-reducing variants and selection for short stature in Sardinia Journal Article Nature Genetics, 47 (11), pp. 1352–1356, 2015, ISSN: 1546-1718. @article{zoledziewska_height-reducing_2015, title = {Height-reducing variants and selection for short stature in Sardinia}, author = {Magdalena Zoledziewska and Carlo Sidore and Charleston W K Chiang and Serena Sanna and Antonella Mulas and Maristella Steri and Fabio Busonero and Joseph H Marcus and Michele Marongiu and Andrea Maschio and Diego Ortega {Del Vecchyo} and Matteo Floris and Antonella Meloni and Alessandro Delitala and Maria Pina Concas and Federico Murgia and Ginevra Biino and Simona Vaccargiu and Ramaiah Nagaraja and Kirk E Lohmueller and UK10K Consortium and Nicholas J Timpson and Nicole Soranzo and Ioanna Tachmazidou and George Dedoussis and Eleftheria Zeggini and Understanding Society Scientific Group and Sergio Uzzau and Chris Jones and Robert Lyons and Andrea Angius and Gon{ç}alo R Abecasis and John Novembre and David Schlessinger and Francesco Cucca}, doi = {10.1038/ng.3403}, issn = {1546-1718}, year = {2015}, date = {2015-11-01}, journal = {Nature Genetics}, volume = {47}, number = {11}, pages = {1352--1356}, abstract = {We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals. |
Orrù, Valeria; Steri, Maristella; Sole, Gabriella; Sidore, Carlo; Virdis, Francesca; Dei, Mariano; Lai, Sandra; Zoledziewska, Magdalena; Busonero, Fabio; Mulas, Antonella; Floris, Matteo; Mentzen, Wieslawa I; Urru, Silvana A M; Olla, Stefania; Marongiu, Michele; Piras, Maria G; Lobina, Monia; Maschio, Andrea; Pitzalis, Maristella; Urru, Maria F; Marcelli, Marco; Cusano, Roberto; Deidda, Francesca; Serra, Valentina; Oppo, Manuela; Pilu, Rosella; Reinier, Frederic; Berutti, Riccardo; Pireddu, Luca; Zara, Ilenia; Porcu, Eleonora; Kwong, Alan; Brennan, Christine; Tarrier, Brendan; Lyons, Robert; Kang, Hyun M; Uzzau, Sergio; Atzeni, Rossano; Valentini, Maria; Firinu, Davide; Leoni, Lidia; Rotta, Gianluca; Naitza, Silvia; Angius, Andrea; Congia, Mauro; Whalen, Michael B; Jones, Chris M; Schlessinger, David; ç, Gon; Fiorillo, Edoardo; Sanna, Serena; Cucca, Francesco Genetic variants regulating immune cell levels in health and disease. Journal Article Cell, 155 (1), pp. 242–56, 2013, ISSN: 1097-4172. @article{orru_genetic_2013, title = {Genetic variants regulating immune cell levels in health and disease.}, author = {Valeria Orrù and Maristella Steri and Gabriella Sole and Carlo Sidore and Francesca Virdis and Mariano Dei and Sandra Lai and Magdalena Zoledziewska and Fabio Busonero and Antonella Mulas and Matteo Floris and Wieslawa I Mentzen and Silvana A M Urru and Stefania Olla and Michele Marongiu and Maria G Piras and Monia Lobina and Andrea Maschio and Maristella Pitzalis and Maria F Urru and Marco Marcelli and Roberto Cusano and Francesca Deidda and Valentina Serra and Manuela Oppo and Rosella Pilu and Frederic Reinier and Riccardo Berutti and Luca Pireddu and Ilenia Zara and Eleonora Porcu and Alan Kwong and Christine Brennan and Brendan Tarrier and Robert Lyons and Hyun M Kang and Sergio Uzzau and Rossano Atzeni and Maria Valentini and Davide Firinu and Lidia Leoni and Gianluca Rotta and Silvia Naitza and Andrea Angius and Mauro Congia and Michael B Whalen and Chris M Jones and David Schlessinger and Gon{ç}alo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco Cucca}, doi = {10.1016/j.cell.2013.08.041}, issn = {1097-4172}, year = {2013}, date = {2013-09-01}, journal = {Cell}, volume = {155}, number = {1}, pages = {242--56}, abstract = {The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease. |
Francalacci, Paolo; Morelli, Laura; Angius, Andrea; Berutti, Riccardo; Reinier, Frederic; Atzeni, Rossano; Pilu, Rosella; Busonero, Fabio; Maschio, Andrea; Zara, Ilenia; Sanna, Daria; Useli, Antonella; Urru, Maria Francesca; Marcelli, Marco; Cusano, Roberto; Oppo, Manuela; Zoledziewska, Magdalena; Pitzalis, Maristella; Deidda, Francesca; Porcu, Eleonora; Poddie, Fausto; Kang, Hyun Min; Lyons, Robert; Tarrier, Brendan; Gresham, Jennifer Bragg; Li, Bingshan; Tofanelli, Sergio; Alonso, Santos; Dei, Mariano; Lai, Sandra; Mulas, Antonella; Whalen, Michael B; Uzzau, Sergio; Jones, Chris; Schlessinger, David; ç, Gon; Sanna, Serena; Sidore, Carlo; Cucca, Francesco Low-pass DNA sequencing of 1200 Sardinians reconstructs European Y-chromosome phylogeny Journal Article Science (New York, N.Y.), 341 (6145), pp. 565–569, 2013, ISSN: 1095-9203. @article{francalacci_low-pass_2013, title = {Low-pass DNA sequencing of 1200 Sardinians reconstructs European Y-chromosome phylogeny}, author = {Paolo Francalacci and Laura Morelli and Andrea Angius and Riccardo Berutti and Frederic Reinier and Rossano Atzeni and Rosella Pilu and Fabio Busonero and Andrea Maschio and Ilenia Zara and Daria Sanna and Antonella Useli and Maria Francesca Urru and Marco Marcelli and Roberto Cusano and Manuela Oppo and Magdalena Zoledziewska and Maristella Pitzalis and Francesca Deidda and Eleonora Porcu and Fausto Poddie and Hyun Min Kang and Robert Lyons and Brendan Tarrier and Jennifer Bragg Gresham and Bingshan Li and Sergio Tofanelli and Santos Alonso and Mariano Dei and Sandra Lai and Antonella Mulas and Michael B Whalen and Sergio Uzzau and Chris Jones and David Schlessinger and Gon{ç}alo R Abecasis and Serena Sanna and Carlo Sidore and Francesco Cucca}, doi = {10.1126/science.1237947}, issn = {1095-9203}, year = {2013}, date = {2013-08-01}, journal = {Science (New York, N.Y.)}, volume = {341}, number = {6145}, pages = {565--569}, abstract = {Genetic variation within the male-specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. Population sequencing of 1204 Sardinian males identified 11,763 MSY single-nucleotide polymorphisms, 6751 of which have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe, along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population textasciitilde7700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal the presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of textasciitilde180,000 to 200,000 years ago, which is consistent with previous mitochondrial DNA-based estimates.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genetic variation within the male-specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. Population sequencing of 1204 Sardinian males identified 11,763 MSY single-nucleotide polymorphisms, 6751 of which have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe, along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population textasciitilde7700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal the presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of textasciitilde180,000 to 200,000 years ago, which is consistent with previous mitochondrial DNA-based estimates. |
Naitza, Silvia ; Porcu, Eleonora ; Steri, Maristella ; Taub, Dennis D; Mulas, Antonella ; Xiao, Xiang ; Strait, James ; Dei, Mariano ; Lai, Sandra ; Busonero, Fabio ; Maschio, Andrea ; Usala, Gianluca ; Zoledziewska, Magdalena ; Sidore, Carlo ; Zara, Ilenia ; Pitzalis, Maristella ; Loi, Alessia ; Virdis, Francesca ; Piras, Roberta ; Deidda, Francesca ; Whalen, Michael B; Crisponi, Laura ; Concas, Antonio ; Podda, Carlo ; Uzzau, Sergio ; Scheet, Paul ; Longo, Dan L; Lakatta, Edward ; Abecasis, Gon{ç}alo R; Cao, Antonio ; Schlessinger, David ; Uda, Manuela ; Sanna, Serena ; Cucca, Francesco A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. Journal Article PLoS genetics, 8 (1), pp. e1002480, 2012, ISSN: 1553-7404. @article{Naitza2012, title = {A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.}, author = {Naitza, Silvia and Porcu, Eleonora and Steri, Maristella and Taub, Dennis D and Mulas, Antonella and Xiao, Xiang and Strait, James and Dei, Mariano and Lai, Sandra and Busonero, Fabio and Maschio, Andrea and Usala, Gianluca and Zoledziewska, Magdalena and Sidore, Carlo and Zara, Ilenia and Pitzalis, Maristella and Loi, Alessia and Virdis, Francesca and Piras, Roberta and Deidda, Francesca and Whalen, Michael B and Crisponi, Laura and Concas, Antonio and Podda, Carlo and Uzzau, Sergio and Scheet, Paul and Longo, Dan L and Lakatta, Edward and Abecasis, Gon{ç}alo R and Cao, Antonio and Schlessinger, David and Uda, Manuela and Sanna, Serena and Cucca, Francesco}, editor = {Sabeti, Pardis C.}, url = {http://dx.plos.org/10.1371/journal.pgen.1002480 http://www.ncbi.nlm.nih.gov/pubmed/22291609 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3266885}, doi = {10.1371/journal.pgen.1002480}, issn = {1553-7404}, year = {2012}, date = {2012-01-01}, journal = {PLoS genetics}, volume = {8}, number = {1}, pages = {e1002480}, abstract = {Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process. |
Sanna, Serena ; Pitzalis, Maristella ; Zoledziewska, Magdalena ; Zara, Ilenia ; Sidore, Carlo ; Murru, Raffaele ; Whalen, Michael B; Busonero, Fabio ; Maschio, Andrea ; Costa, Gianna ; Melis, Maria Cristina ; Deidda, Francesca ; Poddie, Fausto ; Morelli, Laura ; Farina, Gabriele ; Li, Yun ; Dei, Mariano ; Lai, Sandra ; Mulas, Antonella ; Cuccuru, Gianmauro ; Porcu, Eleonora ; Liang, Liming ; Zavattari, Patrizia ; Moi, Loredana ; Deriu, Elisa ; Urru, Francesca M; Bajorek, Michele ; Satta, Maria Anna ; Cocco, Eleonora ; Ferrigno, Paola ; Sotgiu, Stefano ; Pugliatti, Maura ; Traccis, Sebastiano ; Angius, Andrea ; Melis, Maurizio ; Rosati, Giulio ; Abecasis, Gon{ç}alo R; Uda, Manuela ; Marrosu, Maria Giovanna ; Schlessinger, David ; Cucca, Francesco Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis. Journal Article Nature genetics, 42 (6), pp. 495–7, 2010, ISSN: 1546-1718. @article{Sanna2010, title = {Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis.}, author = {Sanna, Serena and Pitzalis, Maristella and Zoledziewska, Magdalena and Zara, Ilenia and Sidore, Carlo and Murru, Raffaele and Whalen, Michael B and Busonero, Fabio and Maschio, Andrea and Costa, Gianna and Melis, Maria Cristina and Deidda, Francesca and Poddie, Fausto and Morelli, Laura and Farina, Gabriele and Li, Yun and Dei, Mariano and Lai, Sandra and Mulas, Antonella and Cuccuru, Gianmauro and Porcu, Eleonora and Liang, Liming and Zavattari, Patrizia and Moi, Loredana and Deriu, Elisa and Urru, M Francesca and Bajorek, Michele and Satta, Maria Anna and Cocco, Eleonora and Ferrigno, Paola and Sotgiu, Stefano and Pugliatti, Maura and Traccis, Sebastiano and Angius, Andrea and Melis, Maurizio and Rosati, Giulio and Abecasis, Gon{ç}alo R and Uda, Manuela and Marrosu, Maria Giovanna and Schlessinger, David and Cucca, Francesco}, url = {http://www.nature.com/doifinder/10.1038/ng.584 http://www.ncbi.nlm.nih.gov/pubmed/20453840 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3786343}, doi = {10.1038/ng.584}, issn = {1546-1718}, year = {2010}, date = {2010-06-01}, journal = {Nature genetics}, volume = {42}, number = {6}, pages = {495--7}, abstract = {A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10)}, keywords = {}, pubstate = {published}, tppubtype = {article} } A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10) |
Zoledziewska, M; Costa, G; Pitzalis, M; Cocco, E; Melis, C; Moi, L; Zavattari, P; Murru, R; Lampis, R; Morelli, L; Poddie, F; Frongia, P; Pusceddu, P; Bajorek, M; Marras, A; Satta, A M; Chessa, A; Pugliatti, M; Sotgiu, S; Whalen, M B; Rosati, G; Cucca, F; Marrosu, M G Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia. Journal Article Genes and immunity, 10 (1), pp. 15–7, 2009, ISSN: 1476-5470. @article{Zoledziewska2009, title = {Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.}, author = {Zoledziewska, M and Costa, G and Pitzalis, M and Cocco, E and Melis, C and Moi, L and Zavattari, P and Murru, R and Lampis, R and Morelli, L and Poddie, F and Frongia, P and Pusceddu, P and Bajorek, M and Marras, A and Satta, A M and Chessa, A and Pugliatti, M and Sotgiu, S and Whalen, M B and Rosati, G and Cucca, F and Marrosu, M G}, url = {http://www.nature.com/doifinder/10.1038/gene.2008.84 http://www.ncbi.nlm.nih.gov/pubmed/18946483}, doi = {10.1038/gene.2008.84}, issn = {1476-5470}, year = {2009}, date = {2009-01-01}, journal = {Genes and immunity}, volume = {10}, number = {1}, pages = {15--7}, abstract = {Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway. |
Zoledziewska, Magdalena ; Perra, Chiara ; Orr{ù}, Valeria ; Moi, Loredana ; Frongia, Paola ; Congia, Mauro ; Bottini, Nunzio ; Cucca, Francesco Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes. Journal Article Diabetes, 57 (1), pp. 229–34, 2008, ISSN: 1939-327X. @article{Zoledziewska2008, title = {Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes.}, author = {Zoledziewska, Magdalena and Perra, Chiara and Orr{ù}, Valeria and Moi, Loredana and Frongia, Paola and Congia, Mauro and Bottini, Nunzio and Cucca, Francesco}, url = {http://diabetes.diabetesjournals.org/cgi/doi/10.2337/db07-0289 http://www.ncbi.nlm.nih.gov/pubmed/17934143}, doi = {10.2337/db07-0289}, issn = {1939-327X}, year = {2008}, date = {2008-01-01}, journal = {Diabetes}, volume = {57}, number = {1}, pages = {229--34}, abstract = {OBJECTIVE The minor allele of the nonsynonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is positively associated with type 1 diabetes and other autoimmune diseases. Genetic and functional data underline its causal effect, but some studies suggest that this polymorphism does not entirely explain disease association of the PTPN22 region. The aim of this study was to evaluate type 1 diabetes association within this gene in the Sardinian population. RESEARCH DESIGN AND METHODS We resequenced the exons and potentially relevant portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 deletion insertion polymorphism [DIP]), 8 of which were novel. A representative set of 14 SNPs and the DIP were sequentially genotyped and assessed for disease association in 794 families, 490 sporadic patients, and 721 matched control subjects. RESULTS The +1858C>T variant, albeit rare in the general Sardinian population (allele frequency 0.014), was positively associated with type 1 diabetes (P(one tail) = 3.7 x 10(-3)). In contrast, the background haplotype in which this mutation occurred was common (haplotype frequency 0.117) and neutrally associated with disease. We did not confirm disease associations reported in other populations for non +1858C>T variants (rs2488457, rs1310182, and rs3811021), although they were present in appreciable frequencies in Sardinia. Additional weak disease associations with rare variants were detected in the Sardinian families but not confirmed in independent case-control sample sets and are most likely spurious. CONCLUSIONS We provide further evidence that the +1858C>T polymorphism is primarily associated with type 1 diabetes and exclude major contributions from other purportedly relevant variants within this gene.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE The minor allele of the nonsynonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is positively associated with type 1 diabetes and other autoimmune diseases. Genetic and functional data underline its causal effect, but some studies suggest that this polymorphism does not entirely explain disease association of the PTPN22 region. The aim of this study was to evaluate type 1 diabetes association within this gene in the Sardinian population. RESEARCH DESIGN AND METHODS We resequenced the exons and potentially relevant portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 deletion insertion polymorphism [DIP]), 8 of which were novel. A representative set of 14 SNPs and the DIP were sequentially genotyped and assessed for disease association in 794 families, 490 sporadic patients, and 721 matched control subjects. RESULTS The +1858C>T variant, albeit rare in the general Sardinian population (allele frequency 0.014), was positively associated with type 1 diabetes (P(one tail) = 3.7 x 10(-3)). In contrast, the background haplotype in which this mutation occurred was common (haplotype frequency 0.117) and neutrally associated with disease. We did not confirm disease associations reported in other populations for non +1858C>T variants (rs2488457, rs1310182, and rs3811021), although they were present in appreciable frequencies in Sardinia. Additional weak disease associations with rare variants were detected in the Sardinian families but not confirmed in independent case-control sample sets and are most likely spurious. CONCLUSIONS We provide further evidence that the +1858C>T polymorphism is primarily associated with type 1 diabetes and exclude major contributions from other purportedly relevant variants within this gene. |
Bottini, Nunzio ; Vang, Torkel ; Cucca, Francesco ; Mustelin, Tomas Role of PTPN22 in type 1 diabetes and other autoimmune diseases Journal Article Seminars in Immunology, 18 (4), pp. 207–213, 2006, ISSN: 10445323. @article{Bottini2006, title = {Role of PTPN22 in type 1 diabetes and other autoimmune diseases}, author = {Bottini, Nunzio and Vang, Torkel and Cucca, Francesco and Mustelin, Tomas}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16697661 http://linkinghub.elsevier.com/retrieve/pii/S1044532306000455}, doi = {10.1016/j.smim.2006.03.008}, issn = {10445323}, year = {2006}, date = {2006-08-01}, journal = {Seminars in Immunology}, volume = {18}, number = {4}, pages = {207--213}, abstract = {We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease. |
Vang, Torkel ; Congia, Mauro ; Macis, Maria Doloretta ; Musumeci, Lucia ; Orr{ú}, Valeria ; Zavattari, Patrizia ; Nika, Konstantina ; Tautz, Lutz ; Task{é}n, Kjetil ; Cucca, Francesco ; Mustelin, Tomas ; Bottini, Nunzio Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Journal Article Nature genetics, 37 (12), pp. 1317–9, 2005, ISSN: 1061-4036. @article{Vang2005, title = {Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant.}, author = {Vang, Torkel and Congia, Mauro and Macis, Maria Doloretta and Musumeci, Lucia and Orr{ú}, Valeria and Zavattari, Patrizia and Nika, Konstantina and Tautz, Lutz and Task{é}n, Kjetil and Cucca, Francesco and Mustelin, Tomas and Bottini, Nunzio}, url = {http://www.nature.com/doifinder/10.1038/ng1673 http://www.ncbi.nlm.nih.gov/pubmed/16273109}, doi = {10.1038/ng1673}, issn = {1061-4036}, year = {2005}, date = {2005-12-01}, journal = {Nature genetics}, volume = {37}, number = {12}, pages = {1317--9}, abstract = {A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant. |
Marrosu, Maria Giovanna ; Motzo, Costantino ; Murru, Raffaele ; Lampis, Rosanna ; Costa, Gianna ; Zavattari, Patrizia ; Contu, Daniela ; Fadda, Elisabetta ; Cocco, Eleonora ; Cucca, Francesco The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone. Journal Article Human molecular genetics, 13 (23), pp. 2919–24, 2004, ISSN: 0964-6906. @article{Marrosu2004, title = {The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone.}, author = {Marrosu, Maria Giovanna and Motzo, Costantino and Murru, Raffaele and Lampis, Rosanna and Costa, Gianna and Zavattari, Patrizia and Contu, Daniela and Fadda, Elisabetta and Cocco, Eleonora and Cucca, Francesco}, url = {https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddh319 http://www.ncbi.nlm.nih.gov/pubmed/15471889}, doi = {10.1093/hmg/ddh319}, issn = {0964-6906}, year = {2004}, date = {2004-12-01}, journal = {Human molecular genetics}, volume = {13}, number = {23}, pages = {2919--24}, abstract = {Type 1 diabetes (T1D) and multiple sclerosis (MS) are two autoimmune diseases which exhibit a considerably higher incidence in Sardinia compared with the surrounding southern European populations. Surprisingly, a 5-fold increased prevalence of T1D has also been observed in Sardinian MS patients. Susceptibility to both disorders is associated with common variants of the HLA-DRB1 and -DQB1 loci. In this study, we determined the relative contribution of genotype variation of these loci to the co-occurrence of the two disorders in Sardinia. We genotyped 1052 T1D patients and 1049 MS patients (31 of whom also had T1D) together with 1917 ethnically matched controls. On the basis of the absolute risks for T1D of the HLA-DRB1-DQB1 genotypes, we established that these loci would only contribute to a 2-fold increase in T1D prevalence in MS patients. From this evidence, we conclude that shared disease associations due to the HLA-DRB1-DQB1 loci provide only a partial explanation for the observed increased prevalence of T1D in Sardinian MS patients. The data suggest that variation at other non-HLA class II loci, and/or unknown environmental factors contribute significantly to the co-occurrence of these two traits.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Type 1 diabetes (T1D) and multiple sclerosis (MS) are two autoimmune diseases which exhibit a considerably higher incidence in Sardinia compared with the surrounding southern European populations. Surprisingly, a 5-fold increased prevalence of T1D has also been observed in Sardinian MS patients. Susceptibility to both disorders is associated with common variants of the HLA-DRB1 and -DQB1 loci. In this study, we determined the relative contribution of genotype variation of these loci to the co-occurrence of the two disorders in Sardinia. We genotyped 1052 T1D patients and 1049 MS patients (31 of whom also had T1D) together with 1917 ethnically matched controls. On the basis of the absolute risks for T1D of the HLA-DRB1-DQB1 genotypes, we established that these loci would only contribute to a 2-fold increase in T1D prevalence in MS patients. From this evidence, we conclude that shared disease associations due to the HLA-DRB1-DQB1 loci provide only a partial explanation for the observed increased prevalence of T1D in Sardinian MS patients. The data suggest that variation at other non-HLA class II loci, and/or unknown environmental factors contribute significantly to the co-occurrence of these two traits. |
Contu, Daniela ; Morelli, Laura ; Zavattari, Patrizia ; Lampis, Rosanna ; Angius, Efisio ; Frongia, Paola ; Murru, Daniela ; Maioli, Mario ; Francalacci, Paolo ; Todd, John A; Cucca, Francesco Sex-related bias and exclusion mapping of the nonrecombinant portion of chromosome Y in human type 1 diabetes in the isolated founder population of Sardinia. Journal Article Diabetes, 51 (12), pp. 3573–3576, 2002, ISSN: 0012-1797 0012-1797. @article{contu_sex-related_2002, title = {Sex-related bias and exclusion mapping of the nonrecombinant portion of chromosome Y in human type 1 diabetes in the isolated founder population of Sardinia.}, author = {Contu, Daniela and Morelli, Laura and Zavattari, Patrizia and Lampis, Rosanna and Angius, Efisio and Frongia, Paola and Murru, Daniela and Maioli, Mario and Francalacci, Paolo and Todd, John A. and Cucca, Francesco}, issn = {0012-1797 0012-1797}, year = {2002}, date = {2002-12-01}, journal = {Diabetes}, volume = {51}, number = {12}, pages = {3573--3576}, abstract = {A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male- to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3}, keywords = {}, pubstate = {published}, tppubtype = {article} } A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male- to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3 |
Marrosu, M G; Murru, R; Murru, M R; Costa, G; Zavattari, P; Whalen, M; Cocco, E; Mancosu, C; Schirru, L; Solla, E; Fadda, E; Melis, C; Porru, I; Rolesu, M; Cucca, F Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Journal Article Human molecular genetics, 10 (25), pp. 2907–16, 2001, ISSN: 0964-6906. @article{Marrosu2001, title = {Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.}, author = {Marrosu, M G and Murru, R and Murru, M R and Costa, G and Zavattari, P and Whalen, M and Cocco, E and Mancosu, C and Schirru, L and Solla, E and Fadda, E and Melis, C and Porru, I and Rolesu, M and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11741834}, issn = {0964-6906}, year = {2001}, date = {2001-12-01}, journal = {Human molecular genetics}, volume = {10}, number = {25}, pages = {2907--16}, abstract = {Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS. |
Cucca, F; Dudbridge, F; Loddo, M; Mulargia, A P; Lampis, R; Angius, E; {De Virgiliis}, S; Koeleman, B P; Bain, S C; Barnett, A H; Gilchrist, F; Cordell, H; Welsh, K; Todd, J A The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1. Journal Article Diabetes, 50 (5), pp. 1200–5, 2001, ISSN: 0012-1797. @article{Cucca2001, title = {The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1.}, author = {Cucca, F and Dudbridge, F and Loddo, M and Mulargia, A P and Lampis, R and Angius, E and {De Virgiliis}, S and Koeleman, B P and Bain, S C and Barnett, A H and Gilchrist, F and Cordell, H and Welsh, K and Todd, J A}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11334427}, issn = {0012-1797}, year = {2001}, date = {2001-05-01}, journal = {Diabetes}, volume = {50}, number = {5}, pages = {1200--5}, abstract = {The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1. |
Zavattari, P; Lampis, R; Motzo, C; Loddo, M; Mulargia, A; Whalen, M; Maioli, M; Angius, E; Todd, J A; Cucca, F Human molecular genetics, 10 (8), pp. 881–9, 2001, ISSN: 0964-6906. @article{Zavattari2001, title = {Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci.}, author = {Zavattari, P and Lampis, R and Motzo, C and Loddo, M and Mulargia, A and Whalen, M and Maioli, M and Angius, E and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11285254}, issn = {0964-6906}, year = {2001}, date = {2001-04-01}, journal = {Human molecular genetics}, volume = {10}, number = {8}, pages = {881--9}, abstract = {Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits. |
Cucca, F; Lampis, R; Congia, M; Angius, E; Nutland, S; Bain, S C; Barnett, A H; Todd, J A A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Journal Article Hum Mol Genet, 10 (19), pp. 2025–2037, 2001, ISSN: 0964-6906 0964-6906. @article{cucca_correlation_2001, title = {A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.}, author = {Cucca, F. and Lampis, R. and Congia, M. and Angius, E. and Nutland, S. and Bain, S. C. and Barnett, A. H. and Todd, J. A.}, issn = {0964-6906 0964-6906}, year = {2001}, date = {2001-01-01}, journal = {Hum Mol Genet}, volume = {10}, number = {19}, pages = {2025--2037}, abstract = {In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D. |
Zavattari, P; Lampis, R; Mulargia, A; Loddo, M; Angius, E; Todd, J A; Cucca, F Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia. Journal Article Human molecular genetics, 9 (20), pp. 2967–72, 2000, ISSN: 0964-6906. @article{Zavattari2000, title = {Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia.}, author = {Zavattari, P and Lampis, R and Mulargia, A and Loddo, M and Angius, E and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11115840}, issn = {0964-6906}, year = {2000}, date = {2000-12-01}, journal = {Human molecular genetics}, volume = {9}, number = {20}, pages = {2967--72}, abstract = {There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapped with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known to be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a validation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatellite markers, we determined the peak of LD to be located at marker D6S2447, which is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defining allelic variation at functional candidate genes within the critical region. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the class II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping.}, keywords = {}, pubstate = {published}, tppubtype = {article} } There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapped with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known to be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a validation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatellite markers, we determined the peak of LD to be located at marker D6S2447, which is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defining allelic variation at functional candidate genes within the critical region. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the class II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping. |
Zavattari, P; Deidda, E; Whalen, M; Lampis, R; Mulargia, A; Loddo, M; Eaves, I; Mastio, G; Todd, J A; Cucca, F Human molecular genetics, 9 (20), pp. 2947–57, 2000, ISSN: 0964-6906. @article{Zavattari2000a, title = {Major factors influencing linkage disequilibrium by analysis of different chromosome regions in distinct populations: demography, chromosome recombination frequency and selection.}, author = {Zavattari, P and Deidda, E and Whalen, M and Lampis, R and Mulargia, A and Loddo, M and Eaves, I and Mastio, G and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11115838}, issn = {0964-6906}, year = {2000}, date = {2000-12-01}, journal = {Human molecular genetics}, volume = {9}, number = {20}, pages = {2947--57}, abstract = {Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations. |
Lampis, R; Morelli, L; Congia, M; Macis, M D; Mulargia, A; Loddo, M; {De Virgiliis}, S; Marrosu, M G; Todd, J A; Cucca, F Human molecular genetics, 9 (20), pp. 2959–65, 2000, ISSN: 0964-6906. @article{Lampis2000, title = {The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases.}, author = {Lampis, R and Morelli, L and Congia, M and Macis, M D and Mulargia, A and Loddo, M and {De Virgiliis}, S and Marrosu, M G and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11115839}, issn = {0964-6906}, year = {2000}, date = {2000-12-01}, journal = {Human molecular genetics}, volume = {9}, number = {20}, pages = {2959--65}, abstract = {We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs. |
Eaves, I A; Merriman, T R; Barber, R A; Nutland, S; Tuomilehto-Wolf, E; Tuomilehto, J; Cucca, F; Todd, J A The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes. Journal Article Nat Genet, 25 (3), pp. 320–323, 2000, ISSN: 1061-4036 1061-4036. @article{eaves_genetically_2000, title = {The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes.}, author = {Eaves, I. A. and Merriman, T. R. and Barber, R. A. and Nutland, S. and Tuomilehto-Wolf, E. and Tuomilehto, J. and Cucca, F. and Todd, J. A.}, doi = {10.1038/77091}, issn = {1061-4036 1061-4036}, year = {2000}, date = {2000-07-01}, journal = {Nat Genet}, volume = {25}, number = {3}, pages = {320--323}, abstract = {The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease. |
Cucca, F; Esposito, L; Goy, J V; Merriman, M E; Wilson, A J; Reed, P W; Bain, S C; Todd, J A Diabetes, 47 (9), pp. 1525–7, 1998, ISSN: 0012-1797. @article{Cucca1998a, title = {Investigation of linkage of chromosome 8 to type 1 diabetes: multipoint analysis and exclusion mapping of human chromosome 8 in 593 affected sib-pair families from the U.K. and U.S.}, author = {Cucca, F and Esposito, L and Goy, J V and Merriman, M E and Wilson, A J and Reed, P W and Bain, S C and Todd, J A}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9726245}, issn = {0012-1797}, year = {1998}, date = {1998-09-01}, journal = {Diabetes}, volume = {47}, number = {9}, pages = {1525--7}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Marrosu, M G; Murru, M R; Costa, G; Murru, R; Muntoni, F; Cucca, F DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. Journal Article Human molecular genetics, 7 (8), pp. 1235–7, 1998, ISSN: 0964-6906. @article{Marrosu1998, title = {DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population.}, author = {Marrosu, M G and Murru, M R and Costa, G and Murru, R and Muntoni, F and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9668164}, issn = {0964-6906}, year = {1998}, date = {1998-08-01}, journal = {Human molecular genetics}, volume = {7}, number = {8}, pages = {1235--7}, abstract = {Multiple sclerosis (MS) is a common neurological disease caused by genetic and environmental factors. Previous genetic analyses have suggested that theMHC/HLA region on chromosome 6p21 contains an MS-predisposing component. Which of the many genes present in this region is primarily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the Mediterranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition. Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian-specific DRB1*0405(DR4)- DQA1*0501-DQB1*0301 haplotype and the DRB1* 0301(DR3)-DQA1*0501-DQB1*0201 haplotype. Detailed comparative analysis of the DRB1-DQA1- DQB1 haplotypes present in this data set did not identify an individual locus that could explain MS susceptibility. The predisposing effect is haplotype specific, in that it is confined to specific combinations of alleles at the DRB1, DQA1 and DQB1 loci. Cross-ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These results suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsible for genetic susceptibility to MS. Alternatively, the presence of complex interactions between different HLA haplotypes, other non-HLA predisposing genes and environmental factors may explain different associations in different populations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Multiple sclerosis (MS) is a common neurological disease caused by genetic and environmental factors. Previous genetic analyses have suggested that theMHC/HLA region on chromosome 6p21 contains an MS-predisposing component. Which of the many genes present in this region is primarily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the Mediterranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition. Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian-specific DRB1*0405(DR4)- DQA1*0501-DQB1*0301 haplotype and the DRB1* 0301(DR3)-DQA1*0501-DQB1*0201 haplotype. Detailed comparative analysis of the DRB1-DQA1- DQB1 haplotypes present in this data set did not identify an individual locus that could explain MS susceptibility. The predisposing effect is haplotype specific, in that it is confined to specific combinations of alleles at the DRB1, DQA1 and DQB1 loci. Cross-ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These results suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsible for genetic susceptibility to MS. Alternatively, the presence of complex interactions between different HLA haplotypes, other non-HLA predisposing genes and environmental factors may explain different associations in different populations. |
Cucca, F; Goy, J V; Kawaguchi, Y; Esposito, L; Merriman, M E; Wilson, A J; Cordell, H J; Bain, S C; Todd, J A A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Journal Article Nature genetics, 19 (3), pp. 301–2, 1998, ISSN: 1061-4036. @article{Cucca1998, title = {A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients.}, author = {Cucca, F and Goy, J V and Kawaguchi, Y and Esposito, L and Merriman, M E and Wilson, A J and Cordell, H J and Bain, S C and Todd, J A}, url = {http://www.nature.com/doifinder/10.1038/995 http://www.ncbi.nlm.nih.gov/pubmed/9662410}, doi = {10.1038/995}, issn = {1061-4036}, year = {1998}, date = {1998-07-01}, journal = {Nature genetics}, volume = {19}, number = {3}, pages = {301--2}, abstract = {It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X not = DR4) with a M:F ratio of 1.7 (P=9.3x10(-7)), compared with a ratio of 1.0 in the DR4/Y category (Y;DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5}, keywords = {}, pubstate = {published}, tppubtype = {article} } It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X not = DR4) with a M:F ratio of 1.7 (P=9.3x10(-7)), compared with a ratio of 1.0 in the DR4/Y category (Y;DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5 |
Cucca, F; Lampis, R; Frau, F; Macis, D; Angius, E; Masile, P; Chessa, M; Frongia, P; Silvetti, M; Cao, A; {De Virgiliis}, S; Congia, M The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci. Journal Article Human immunology, 43 (4), pp. 301–8, 1995, ISSN: 0198-8859. @article{Cucca1995, title = {The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci.}, author = {Cucca, F and Lampis, R and Frau, F and Macis, D and Angius, E and Masile, P and Chessa, M and Frongia, P and Silvetti, M and Cao, A and {De Virgiliis}, S and Congia, M}, url = {http://www.ncbi.nlm.nih.gov/pubmed/7499178}, issn = {0198-8859}, year = {1995}, date = {1995-08-01}, journal = {Human immunology}, volume = {43}, number = {4}, pages = {301--8}, abstract = {The contribution of genetic variation at HLA class II loci to the susceptibility to and protection from IDDM was investigated by analyzing the distribution of HLA-DRB1*04 haplotypes in 630 Sardinian newborns and 155 Sardinian IDDM patients. The different RRs and ARs of the various DR4-DQB1*0302 haplotypes, significantly ranging from the strongly associated DRB1*0405, DQB1*0302 to the protective DRB1*0403, DQB1*0302 haplotypes, provides clearcut evidence that the DRB1 locus is crucial in conferring IDDM predisposition or protection. Also, the DQB1 locus influences IDDM predisposition or protection by restricting the disease-positive association to DRB1*0405 haplotypes carrying the susceptibility DQB1*0302 or DQB1*0201 alleles but not the protective DQB1*0301 allele. Haplotype analysis not only suggests that the DRB1 and DQB1 loci influence IDDM risk in the same way, but also that the HLA-linked protection is "dominant" compared with "susceptibility." These results, obtained from a population with one of the highest IDDM incidences in the world, define more clearly the contribution of the various HLA loci to IDDM protection or susceptibility and allow a more precise calculation of AR.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The contribution of genetic variation at HLA class II loci to the susceptibility to and protection from IDDM was investigated by analyzing the distribution of HLA-DRB1*04 haplotypes in 630 Sardinian newborns and 155 Sardinian IDDM patients. The different RRs and ARs of the various DR4-DQB1*0302 haplotypes, significantly ranging from the strongly associated DRB1*0405, DQB1*0302 to the protective DRB1*0403, DQB1*0302 haplotypes, provides clearcut evidence that the DRB1 locus is crucial in conferring IDDM predisposition or protection. Also, the DQB1 locus influences IDDM predisposition or protection by restricting the disease-positive association to DRB1*0405 haplotypes carrying the susceptibility DQB1*0302 or DQB1*0201 alleles but not the protective DQB1*0301 allele. Haplotype analysis not only suggests that the DRB1 and DQB1 loci influence IDDM risk in the same way, but also that the HLA-linked protection is "dominant" compared with "susceptibility." These results, obtained from a population with one of the highest IDDM incidences in the world, define more clearly the contribution of the various HLA loci to IDDM protection or susceptibility and allow a more precise calculation of AR. |
Copeman, J B; Cucca, F; Hearne, C M; Cornall, R J; Reed, P W; R{ø}nningen, K S; Undlien, D E; Nistic{ò}, L; Buzzetti, R; Tosi, R; Pociot, F; Nerup, J; Corn{é}lis, F; Barnett, A H; Bain, S C; Todd, J A Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31–q33 Journal Article Nature Genetics, 9 (1), pp. 80–85, 1995, ISSN: 1061-4036. @article{Copeman1995, title = {Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31–q33}, author = {Copeman, J.B. and Cucca, F. and Hearne, C.M. and Cornall, R.J. and Reed, P.W. and R{ø}nningen, K.S. and Undlien, D.E. and Nistic{ò}, L. and Buzzetti, R. and Tosi, R. and Pociot, F. and Nerup, J. and Corn{é}lis, F. and Barnett, A.H. and Bain, S.C. and Todd, J.A.}, url = {http://www.ncbi.nlm.nih.gov/pubmed/7704030 http://www.nature.com/doifinder/10.1038/ng0195-80}, doi = {10.1038/ng0195-80}, issn = {1061-4036}, year = {1995}, date = {1995-01-01}, journal = {Nature Genetics}, volume = {9}, number = {1}, pages = {80--85}, abstract = {The role of human chromosome 2 in type 1 diabetes was evaluated by analysing linkage and linkage disequilibrium at 21 microsatellite marker loci, using 348 affected sibpair families and 107 simplex families. The microsatellite D2S152 was linked to, and associated with, disease in families from three different populations. Our evidence localizes a new diabetes susceptibility gene, IDDM7, to within two centiMorgans of D2S152. This places it in a region of chromosome 2q that shows conserved synteny with the region of mouse chromosome 1 containing the murine type 1 diabetes gene, Idd5. These results demonstrate the utility of polymorphic microsatellites for linkage disequilibrium mapping of genes for complex diseases.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The role of human chromosome 2 in type 1 diabetes was evaluated by analysing linkage and linkage disequilibrium at 21 microsatellite marker loci, using 348 affected sibpair families and 107 simplex families. The microsatellite D2S152 was linked to, and associated with, disease in families from three different populations. Our evidence localizes a new diabetes susceptibility gene, IDDM7, to within two centiMorgans of D2S152. This places it in a region of chromosome 2q that shows conserved synteny with the region of mouse chromosome 1 containing the murine type 1 diabetes gene, Idd5. These results demonstrate the utility of polymorphic microsatellites for linkage disequilibrium mapping of genes for complex diseases. |
2018 |
Idda, M L; Lodde, V; McClusky, W G; Martindale, J L; Yang, X; Munk, R; Steri, M; Orru, V; Mulas, A; Cucca, F; Abdelmohsen, K; Gorospe, M Cooperative translational control of polymorphic BAFF by NF90 and miR-15a Journal Article Nucleic Acids Res., 46 (22), pp. 12040–12051, 2018. @article{pmid30272251, title = {Cooperative translational control of polymorphic BAFF by NF90 and miR-15a}, author = {M L Idda and V Lodde and W G McClusky and J L Martindale and X Yang and R Munk and M Steri and V Orru and A Mulas and F Cucca and K Abdelmohsen and M Gorospe}, year = {2018}, date = {2018-12-01}, journal = {Nucleic Acids Res.}, volume = {46}, number = {22}, pages = {12040--12051}, abstract = {Polymorphisms in untranslated regions (UTRs) of disease-associated mRNAs can alter protein production. We recently identified a genetic variant in the 3'UTR of the TNFSF13B gene, encoding the cytokine BAFF (B-cell-activating factor), that generates an alternative polyadenylation site yielding a shorter, more actively translated variant, BAFF-var mRNA. Accordingly, individuals bearing the TNFSF13B variant had higher circulating BAFF and elevated risk of developing autoimmune diseases. Here, we investigated the molecular mechanisms controlling the enhanced translation of BAFF-var mRNA. We identified nuclear factor 90 (NF90, also known as ILF3) as an RNA-binding protein that bound preferentially the wild-type (BAFF-WT mRNA) but not BAFF-var mRNA in human monocytic leukemia THP-1 cells. NF90 selectively suppressed BAFF translation by recruiting miR-15a to the 3'UTR of BAFF-WT mRNA. Our results uncover a paradigm whereby an autoimmunity-causing BAFF polymorphism prevents NF90-mediated recruitment of microRNAs to suppress BAFF translation, raising the levels of disease-associated BAFF.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Polymorphisms in untranslated regions (UTRs) of disease-associated mRNAs can alter protein production. We recently identified a genetic variant in the 3'UTR of the TNFSF13B gene, encoding the cytokine BAFF (B-cell-activating factor), that generates an alternative polyadenylation site yielding a shorter, more actively translated variant, BAFF-var mRNA. Accordingly, individuals bearing the TNFSF13B variant had higher circulating BAFF and elevated risk of developing autoimmune diseases. Here, we investigated the molecular mechanisms controlling the enhanced translation of BAFF-var mRNA. We identified nuclear factor 90 (NF90, also known as ILF3) as an RNA-binding protein that bound preferentially the wild-type (BAFF-WT mRNA) but not BAFF-var mRNA in human monocytic leukemia THP-1 cells. NF90 selectively suppressed BAFF translation by recruiting miR-15a to the 3'UTR of BAFF-WT mRNA. Our results uncover a paradigm whereby an autoimmunity-causing BAFF polymorphism prevents NF90-mediated recruitment of microRNAs to suppress BAFF translation, raising the levels of disease-associated BAFF. |
Nilsson, P M; Laurent, S; Cunha, P G; Olsen, M H; Rietzschel, E; Franco, O H; Ryliškytė, L; Strazhesko, I; Vlachopoulos, C; Chen, C H; Boutouyrie, P; Cucca, F; Lakatta, E G; Scuteri, A Characteristics of healthy vascular ageing in pooled population-based cohort studies: the global Metabolic syndrome and Artery REsearch Consortium Journal Article J. Hypertens., 36 (12), pp. 2340–2349, 2018. @article{Nilsson2018, title = {Characteristics of healthy vascular ageing in pooled population-based cohort studies: the global Metabolic syndrome and Artery REsearch Consortium}, author = {P M Nilsson and S Laurent and P G Cunha and M H Olsen and E Rietzschel and O H Franco and L Ryliškytė and I Strazhesko and C Vlachopoulos and C H Chen and P Boutouyrie and F Cucca and E G Lakatta and A Scuteri}, year = {2018}, date = {2018-12-01}, journal = {J. Hypertens.}, volume = {36}, number = {12}, pages = {2340--2349}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Ligthart, S; Vaez, A; Vosa, U; Stathopoulou, M G; de Vries, P S; Prins, B P; der Most, Van P J; Tanaka, T; Naderi, E; Rose, L M; Wu, Y; Karlsson, R; Barbalic, M; Lin, H; Pool, R; Zhu, G; Mace, A; Sidore, C; [...], ; Cucca, F; [...], ; Boerwinkle, E; Rotter, J; Rice, K; Lange, L; Perola, M; de Geus, E; Morris, A P; Makela, K M; Stacey, D; Eriksson, J; Frayling, T M; Slagboom, E P Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders Journal Article 103 (5), pp. 691–706, 2018, ([PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC6218410] [DOI:hrefhttps://dx.doi.org/10.1016/j.ajhg.2018.09.00910.1016/j.ajhg.2018.09.009] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2909416129094161]). @article{pmid30388399, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders}, author = {S Ligthart and A Vaez and U Vosa and M G Stathopoulou and P S de Vries and B P Prins and P J Van der Most and T Tanaka and E Naderi and L M Rose and Y Wu and R Karlsson and M Barbalic and H Lin and R Pool and G Zhu and A Mace and C Sidore and [...] and F Cucca and [...] and E Boerwinkle and J Rotter and K Rice and L Lange and M Perola and E de Geus and A P Morris and K M Makela and D Stacey and J Eriksson and T M Frayling and E P Slagboom}, year = {2018}, date = {2018-11-01}, volume = {103}, number = {5}, pages = {691--706}, abstract = {C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.}, note = {[PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC6218410] [DOI:hrefhttps://dx.doi.org/10.1016/j.ajhg.2018.09.00910.1016/j.ajhg.2018.09.009] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2909416129094161]}, keywords = {}, pubstate = {published}, tppubtype = {article} } C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences. |
Delitala, A P; Steri, M; Fiorillo, E; Marongiu, M; Lakatta, E G; Schlessinger, D; Cucca, F Adipocytokine correlations with thyroid function and autoimmunity in euthyroid sardinians Journal Article Cytokine, 111 , pp. 189–193, 2018. @article{pmid30173124, title = {Adipocytokine correlations with thyroid function and autoimmunity in euthyroid sardinians}, author = {A P Delitala and M Steri and E Fiorillo and M Marongiu and E G Lakatta and D Schlessinger and F Cucca}, year = {2018}, date = {2018-11-01}, journal = {Cytokine}, volume = {111}, pages = {189--193}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Floris, M; Olla, S; Schlessinger, D; Cucca, F Genetic-Driven Druggable Target Identification and Validation Journal Article Trends Genet., 34 (7), pp. 558–570, 2018. @article{pmid29803319, title = {Genetic-Driven Druggable Target Identification and Validation}, author = {M Floris and S Olla and D Schlessinger and F Cucca}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29803319}, year = {2018}, date = {2018-07-01}, journal = {Trends Genet.}, volume = {34}, number = {7}, pages = {558--570}, abstract = {Choosing the right biological target is the critical primary decision for the development of new drugs. Systematic genetic association testing of both human diseases and quantitative traits, along with resultant findings of coincident associations between them, is becoming a powerful approach to infer drug targetable candidates and generate in vitro tests to identify compounds that can modulate them therapeutically. Here, we discuss opportunities and challenges, and infer criteria for the optimal use of genetic findings in the drug discovery pipeline.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Choosing the right biological target is the critical primary decision for the development of new drugs. Systematic genetic association testing of both human diseases and quantitative traits, along with resultant findings of coincident associations between them, is becoming a powerful approach to infer drug targetable candidates and generate in vitro tests to identify compounds that can modulate them therapeutically. Here, we discuss opportunities and challenges, and infer criteria for the optimal use of genetic findings in the drug discovery pipeline. |
Angius, A; Cossu, S; Uva, P; Oppo, M; Onano, S; Persico, I; Fotia, G; Atzeni, R; Cuccuru, G; Asunis, M; Cucca, F; Pruna, D; Crisponi, L Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome Journal Article Clin. Genet., 93 (6), pp. 1245–1247, 2018, ([DOI:hrefhttps://dx.doi.org/10.1111/cge.1316210.1111/cge.13162] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2939978629399786]). @article{pmid29399786, title = {Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome}, author = {Angius, A. and Cossu, S. and Uva, P. and Oppo, M. and Onano, S. and Persico, I. and Fotia, G. and Atzeni, R. and Cuccuru, G. and Asunis, M. and Cucca, F. and Pruna, D. and Crisponi, L.}, year = {2018}, date = {2018-06-01}, journal = {Clin. Genet.}, volume = {93}, number = {6}, pages = {1245--1247}, abstract = {Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1. This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN.}, note = {[DOI:hrefhttps://dx.doi.org/10.1111/cge.1316210.1111/cge.13162] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2939978629399786]}, keywords = {}, pubstate = {published}, tppubtype = {article} } Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1. This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN. |
Angius, A; Cossu, S; Uva, P; Oppo, M; Onano, S; Persico, I; Fotia, G; Atzeni, R; Cuccuru, G; Asunis, M; Cucca, F; Pruna, D; Crisponi, L Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome. Journal Article Clin Genet, 2018, ISSN: 1399-0004 0009-9163. @article{angius_novel_2018, title = {Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome.}, author = {A Angius and S Cossu and P Uva and M Oppo and S Onano and I Persico and G Fotia and R Atzeni and G Cuccuru and M Asunis and F Cucca and D Pruna and L Crisponi}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29399786}, doi = {10.1111/cge.13162}, issn = {1399-0004 0009-9163}, year = {2018}, date = {2018-01-01}, journal = {Clin Genet}, abstract = {Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K(+) and Ca(2+) and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1.This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K(+) and Ca(2+) and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1.This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN. |
Lai, F; Cucca, F; Frau, R; Corrias, F; Schlich, M; Caboni, P; Fadda, A M; Bassareo, V Systemic Administration of Orexin a Loaded Liposomes Potentiates Nucleus Accumbens Shell Đopamine Release by Sucrose Feeding Journal Article Front Psychiatry, 9 , pp. 640, 2018, ([PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287025PMC6287025] [DOI:hrefhttps://dx.doi.org/10.3389/fpsyt.2018.0064010.3389/fpsyt.2018.00640] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3055968330559683]). @article{pmid30559683, title = {Systemic Administration of Orexin a Loaded Liposomes Potentiates Nucleus Accumbens Shell Đopamine Release by Sucrose Feeding}, author = {F Lai and F Cucca and R Frau and F Corrias and M Schlich and P Caboni and A M Fadda and V Bassareo}, year = {2018}, date = {2018-01-01}, journal = {Front Psychiatry}, volume = {9}, pages = {640}, abstract = {Orexin neurons originate in the lateral and dorsomedial hypothalamus and perifornical area and produce two different neuropeptides: orexin A (OxA) and orexin B (OxB), which activate OxR1 and OxR2 receptors. In the lateral hypothalamus (LH) orexin neurons are involved in behavior motivated by natural rewards such as palatable food (sugar, high-fat food) and it has been demonstrated similarly that the orexin signaling in the ventral tegmental area (VTA) is implicated in the intake of high-fat food. The VTA is an important area involved in reward processing. Given the involvement of nucleus accumbens (NAc) shell dopamine (DA) in motivation for food, we intended to investigate the effect of OxA on the basal and feeding-activated DA transmission in the NAc shell. OxA is a large peptide and does not cross the blood-brain barrier and for this reason was loaded on two kinds of liposomes: anti-transferrin-monoclonal antibodies (OX26-mAb) and lactoferrin-modified stealth liposomes. The effect of IV administration of both OxA liposomes on NAc shell DA was studied by microdialysis in freely moving rats. OxA, administered using both kinds of liposomes, produced a delayed and transitory increase in dialysate DA in the NAc shell, strongly and lastingly potentiated the increase in dialysate DA elicited by sucrose pellet consumption and increased the number of eaten pellets. These effects of OxA on DA transmission and feeding were prevented by the OxR1 antagonist SB 334867. Hence, OxA acting on VTA OxR1 can facilitate sucrose-stimulated NAc shell DA transmission directly by increasing the basal activity of VTA DA neurons that send their projections to the NAc shell.}, note = {[PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287025PMC6287025] [DOI:hrefhttps://dx.doi.org/10.3389/fpsyt.2018.0064010.3389/fpsyt.2018.00640] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3055968330559683]}, keywords = {}, pubstate = {published}, tppubtype = {article} } Orexin neurons originate in the lateral and dorsomedial hypothalamus and perifornical area and produce two different neuropeptides: orexin A (OxA) and orexin B (OxB), which activate OxR1 and OxR2 receptors. In the lateral hypothalamus (LH) orexin neurons are involved in behavior motivated by natural rewards such as palatable food (sugar, high-fat food) and it has been demonstrated similarly that the orexin signaling in the ventral tegmental area (VTA) is implicated in the intake of high-fat food. The VTA is an important area involved in reward processing. Given the involvement of nucleus accumbens (NAc) shell dopamine (DA) in motivation for food, we intended to investigate the effect of OxA on the basal and feeding-activated DA transmission in the NAc shell. OxA is a large peptide and does not cross the blood-brain barrier and for this reason was loaded on two kinds of liposomes: anti-transferrin-monoclonal antibodies (OX26-mAb) and lactoferrin-modified stealth liposomes. The effect of IV administration of both OxA liposomes on NAc shell DA was studied by microdialysis in freely moving rats. OxA, administered using both kinds of liposomes, produced a delayed and transitory increase in dialysate DA in the NAc shell, strongly and lastingly potentiated the increase in dialysate DA elicited by sucrose pellet consumption and increased the number of eaten pellets. These effects of OxA on DA transmission and feeding were prevented by the OxR1 antagonist SB 334867. Hence, OxA acting on VTA OxR1 can facilitate sucrose-stimulated NAc shell DA transmission directly by increasing the basal activity of VTA DA neurons that send their projections to the NAc shell. |
Teumer, A; Chaker, L; Groeneweg, S; Li, Y; Munno, Di C; Barbieri, C; Schultheiss, U T; Traglia, M; Ahluwalia, T S; Akiyama, M; Appel, E V R; Arking, D E; Arnold, A; Astrup, A; Beekman, M; Beilby, J P; Bekaert, S; Boerwinkle, E; Brown, S J; Buyzere, De M; Campbell, P J; Ceresini, G; Cerqueira, C; Cucca, F; Deary, I J; Deelen, J; Eckardt, K U; Ekici, A B; Eriksson, J G; Ferrrucci, L; Fiers, T; Fiorillo, E; Ford, I; Fox, C S; Fuchsberger, C; Galesloot, T E; Gieger, C; Gogele, M; Grandi, De A; Grarup, N; Greiser, K H; Haljas, K; Hansen, T; Harris, S E; van Heemst, D; den Heijer, M; Hicks, A A; den Hollander, W; Homuth, G; Hui, J; Ikram, M A; Ittermann, T; Jensen, R A; Jing, J; Jukema, J W; Kajantie, E; Kamatani, Y; Kasbohm, E; Kaufman, J M; Kiemeney, L A; Kloppenburg, M; Kronenberg, F; Kubo, M; Lahti, J; Lapauw, B; Li, S; Liewald, D C M; Lim, E M; Linneberg, A; Marina, M; Mascalzoni, D; Matsuda, K; Medenwald, D; Meisinger, C; Meulenbelt, I; Meyer, De T; Schwabedissen, Meyer Zu H E; Mikolajczyk, R; Moed, M; Netea-Maier, R T; Nolte, I M; Okada, Y; Pala, M; Pattaro, C; Pedersen, O; Petersmann, A; Porcu, E; Postmus, I; Pramstaller, P P; Psaty, B M; Ramos, Y F M; Rawal, R; Redmond, P; Richards, J B; Rietzschel, E R; Rivadeneira, F; Roef, G; Rotter, J I; Sala, C F; Schlessinger, D; Selvin, E; Slagboom, P E; Soranzo, N; S?rensen, T I A; Spector, T D; Starr, J M; Stott, D J; Taes, Y; Taliun, D; Tanaka, T; Thuesen, B; Tiller, D; Toniolo, D; Uitterlinden, A G; Visser, W E; Walsh, J P; Wilson, S G; Wolffenbuttel, B H R; Yang, Q; Zheng, H F; Cappola, A; Peeters, R P; Naitza, S; Volzke, H; Sanna, S; Kottgen, A; Visser, T J; Medici, M; Alizadeh, B Z; Boezen, H M; Franke, L; van der Harst, P; Navis, G; Rots, M; Snieder, H; Swertz, M A; Wijmenga, C Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation Journal Article Nat Commun, 9 (1), pp. 4455, 2018. @article{pmid30367059, title = {Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation}, author = {A Teumer and L Chaker and S Groeneweg and Y Li and C Di Munno and C Barbieri and U T Schultheiss and M Traglia and T S Ahluwalia and M Akiyama and E V R Appel and D E Arking and A Arnold and A Astrup and M Beekman and J P Beilby and S Bekaert and E Boerwinkle and S J Brown and M De Buyzere and P J Campbell and G Ceresini and C Cerqueira and F Cucca and I J Deary and J Deelen and K U Eckardt and A B Ekici and J G Eriksson and L Ferrrucci and T Fiers and E Fiorillo and I Ford and C S Fox and C Fuchsberger and T E Galesloot and C Gieger and M Gogele and A De Grandi and N Grarup and K H Greiser and K Haljas and T Hansen and S E Harris and D van Heemst and M den Heijer and A A Hicks and W den Hollander and G Homuth and J Hui and M A Ikram and T Ittermann and R A Jensen and J Jing and J W Jukema and E Kajantie and Y Kamatani and E Kasbohm and J M Kaufman and L A Kiemeney and M Kloppenburg and F Kronenberg and M Kubo and J Lahti and B Lapauw and S Li and D C M Liewald and E M Lim and A Linneberg and M Marina and D Mascalzoni and K Matsuda and D Medenwald and C Meisinger and I Meulenbelt and T De Meyer and H E Meyer Zu Schwabedissen and R Mikolajczyk and M Moed and R T Netea-Maier and I M Nolte and Y Okada and M Pala and C Pattaro and O Pedersen and A Petersmann and E Porcu and I Postmus and P P Pramstaller and B M Psaty and Y F M Ramos and R Rawal and P Redmond and J B Richards and E R Rietzschel and F Rivadeneira and G Roef and J I Rotter and C F Sala and D Schlessinger and E Selvin and P E Slagboom and N Soranzo and T I A S?rensen and T D Spector and J M Starr and D J Stott and Y Taes and D Taliun and T Tanaka and B Thuesen and D Tiller and D Toniolo and A G Uitterlinden and W E Visser and J P Walsh and S G Wilson and B H R Wolffenbuttel and Q Yang and H F Zheng and A Cappola and R P Peeters and S Naitza and H Volzke and S Sanna and A Kottgen and T J Visser and M Medici and B Z Alizadeh and H M Boezen and L Franke and P van der Harst and G Navis and M Rots and H Snieder and M A Swertz and C Wijmenga}, year = {2018}, date = {2018-01-01}, journal = {Nat Commun}, volume = {9}, number = {1}, pages = {4455}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Evangelou, E; Warren, H R; Mosen-Ansorena, D; Mifsud, B; Pazoki, R; [...], ; Cucca, F; Danesh, J; Hayward, C; Howson, J M M; Laakso, M; Lakatta, E G; Langenberg, C; Melander, O; Mook-Kanamori, D O; Palmer, C N A; Risch, L; Scott, R A; Scott, R J; Sever, P; Spector, T D; van der Harst, P; Wareham, N J; Zeggini, E; Levy, D; Munroe, P B; Newton-Cheh, C; Brown, M J; Metspalu, A; Hung, A M; O'Donnell, C J; Edwards, T L; Psaty, B M; Tzoulaki, I; Barnes, M R; Wain, L V; Elliott, P; Caulfield, M J Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits Journal Article Nat. Genet., 50 (10), pp. 1412–1425, 2018. @article{pmid30224653, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits}, author = {E Evangelou and H R Warren and D Mosen-Ansorena and B Mifsud and R Pazoki and [...] and F Cucca and J Danesh and C Hayward and J M M Howson and M Laakso and E G Lakatta and C Langenberg and O Melander and D O Mook-Kanamori and C N A Palmer and L Risch and R A Scott and R J Scott and P Sever and T D Spector and P van der Harst and N J Wareham and E Zeggini and D Levy and P B Munroe and C Newton-Cheh and M J Brown and A Metspalu and A M Hung and C J O'Donnell and T L Edwards and B M Psaty and I Tzoulaki and M R Barnes and L V Wain and P Elliott and M J Caulfield}, year = {2018}, date = {2018-01-01}, journal = {Nat. Genet.}, volume = {50}, number = {10}, pages = {1412--1425}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Chiang, C W K; Marcus, J H; Sidore, C; Biddanda, A; Al-Asadi, H; Zoledziewska, M; Pitzalis, M; Busonero, F; Maschio, A; Pistis, G; Steri, M; Angius, A; Lohmueller, K E; Abecasis, G R; Schlessinger, D; Cucca, F; Novembre, J Genomic history of the Sardinian population Journal Article Nat. Genet., 50 (10), pp. 1426–1434, 2018. @article{pmid30224645, title = {Genomic history of the Sardinian population}, author = {C W K Chiang and J H Marcus and C Sidore and A Biddanda and H Al-Asadi and M Zoledziewska and M Pitzalis and F Busonero and A Maschio and G Pistis and M Steri and A Angius and K E Lohmueller and G R Abecasis and D Schlessinger and F Cucca and J Novembre}, url = {https://www.nature.com/articles/s41588-018-0215-8}, year = {2018}, date = {2018-01-01}, journal = {Nat. Genet.}, volume = {50}, number = {10}, pages = {1426--1434}, abstract = {The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations. |
Egorov, E S; Kasatskaya, S A; Zubov, V N; Izraelson, M; Nakonechnaya, T O; Staroverov, D B; Angius, A; Cucca, F; Mamedov, I Z; Rosati, E; Franke, A; Shugay, M; Pogorelyy, M V; Chudakov, D M; Britanova, O V The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging Journal Article Front Immunol, 9 , pp. 1618, 2018, ([PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066563PMC6066563] [DOI:hrefhttps://dx.doi.org/10.3389/fimmu.2018.0161810.3389/fimmu.2018.01618] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2457973124579731]). @article{Egorov2018, title = {The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging}, author = {E S Egorov and S A Kasatskaya and V N Zubov and M Izraelson and T O Nakonechnaya and D B Staroverov and A Angius and F Cucca and I Z Mamedov and E Rosati and A Franke and M Shugay and M V Pogorelyy and D M Chudakov and O V Britanova}, year = {2018}, date = {2018-01-01}, journal = {Front Immunol}, volume = {9}, pages = {1618}, abstract = {Human aging is associated with a profound loss of thymus productivity, yet naïve T lymphocytes still maintain their numbers by division in the periphery for many years. The extent of such proliferation may depend on the cytokine environment, including IL-7 and T-cell receptor (TCR) "tonic" signaling mediated by self pMHCs recognition. Additionally, intrinsic properties of distinct subpopulations of naïve T cells could influence the overall dynamics of aging-related changes within the naïve T cell compartment. Here, we investigated the differences in the architecture of TCR beta repertoires for naïve CD4, naïve CD8, naïve CD4+CD25-CD31+ (enriched with recent thymic emigrants, RTE), and mature naïve CD4+CD25-CD31- peripheral blood subsets between young and middle-age/old healthy individuals. In addition to observing the accumulation of clonal expansions (as was shown previously), we reveal several notable changes in the characteristics of T cell repertoire. We observed significant decrease of CDR3 length, NDN insert, and number of non-template added N nucleotides within TCR beta CDR3 with aging, together with a prominent change of physicochemical properties of the central part of CDR3 loop. These changes were similar across CD4, CD8, RTE-enriched, and mature CD4 subsets of naïve T cells, with minimal or no difference observed between the latter two subsets for individuals of the same age group. We also observed an increase in "publicity" (fraction of shared clonotypes) of CD4, but not CD8 naïve T cell repertoires. We propose several explanations for these phenomena built upon previous studies of naïve T-cell homeostasis, and call for further studies of the mechanisms causing the observed changes and of consequences of these changes in respect of the possible holes formed in the landscape of naïve T cell TCR repertoire.}, note = {[PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066563PMC6066563] [DOI:hrefhttps://dx.doi.org/10.3389/fimmu.2018.0161810.3389/fimmu.2018.01618] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2457973124579731]}, keywords = {}, pubstate = {published}, tppubtype = {article} } Human aging is associated with a profound loss of thymus productivity, yet naïve T lymphocytes still maintain their numbers by division in the periphery for many years. The extent of such proliferation may depend on the cytokine environment, including IL-7 and T-cell receptor (TCR) "tonic" signaling mediated by self pMHCs recognition. Additionally, intrinsic properties of distinct subpopulations of naïve T cells could influence the overall dynamics of aging-related changes within the naïve T cell compartment. Here, we investigated the differences in the architecture of TCR beta repertoires for naïve CD4, naïve CD8, naïve CD4+CD25-CD31+ (enriched with recent thymic emigrants, RTE), and mature naïve CD4+CD25-CD31- peripheral blood subsets between young and middle-age/old healthy individuals. In addition to observing the accumulation of clonal expansions (as was shown previously), we reveal several notable changes in the characteristics of T cell repertoire. We observed significant decrease of CDR3 length, NDN insert, and number of non-template added N nucleotides within TCR beta CDR3 with aging, together with a prominent change of physicochemical properties of the central part of CDR3 loop. These changes were similar across CD4, CD8, RTE-enriched, and mature CD4 subsets of naïve T cells, with minimal or no difference observed between the latter two subsets for individuals of the same age group. We also observed an increase in "publicity" (fraction of shared clonotypes) of CD4, but not CD8 naïve T cell repertoires. We propose several explanations for these phenomena built upon previous studies of naïve T-cell homeostasis, and call for further studies of the mechanisms causing the observed changes and of consequences of these changes in respect of the possible holes formed in the landscape of naïve T cell TCR repertoire. |
van Setten, J; Brody, J A; Jamshidi, Y; Swenson, B R; Butler, A M; Campbell, H; Greco, Del F M; Evans, D S; Gibson, Q; Gudbjartsson, D F; Kerr, K F; Krijthe, B P; Lyytikainen, L P; Muller, C; Muller-Nurasyid, M; Nolte, I M; Padmanabhan, S; Ritchie, M D; Robino, A; Smith, A V; Steri, M; Tanaka, T; Teumer, A; Trompet, S; Ulivi, S; Verweij, N; Yin, X; Arnar, D O; Asselbergs, F W; Bader, J S; Barnard, J; Bis, J; Blankenberg, S; Boerwinkle, E; Bradford, Y; Buckley, B M; Chung, M K; Crawford, D; den Hoed, M; Denny, J C; Dominiczak, A F; Ehret, G B; Eijgelsheim, M; Ellinor, P T; Felix, S B; Franco, O H; Franke, L; Harris, T B; Holm, H; Ilaria, G; Iorio, A; Kahonen, M; Kolcic, I; Kors, J A; Lakatta, E G; Launer, L J; Lin, H; Lin, H J; Loos, R J F; Lubitz, S A; Macfarlane, P W; Magnani, J W; Leach, I M; Meitinger, T; Mitchell, B D; Munzel, T; Papanicolaou, G J; Peters, A; Pfeufer, A; Pramstaller, P P; Raitakari, O T; Rotter, J I; Rudan, I; Samani, N J; Schlessinger, D; Aldana, Silva C T; Sinner, M F; Smith, J D; Snieder, H; Soliman, E Z; Spector, T D; Stott, D J; Strauch, K; Tarasov, K V; Thorsteinsdottir, U; Uitterlinden, A G; Wagoner, Van D R; Volker, U; Volzke, H; Waldenberger, M; Westra, Jan H; Wild, P S; Zeller, T; Alonso, A; Avery, C L; Bandinelli, S; Benjamin, E J; Cucca, F; Dorr, M; Ferrucci, L; Gasparini, P; Gudnason, V; Hayward, C; Heckbert, S R; Hicks, A A; Jukema, J W; Kaab, S; Lehtimaki, T; Liu, Y; Munroe, P B; Parsa, A; Polasek, O; Psaty, B M; Roden, D M; Schnabel, R B; Sinagra, G; Stefansson, K; Stricker, B H; van der Harst, P; van Duijn, C M; Wilson, J F; Gharib, S A; de Bakker, P I W; Isaacs, A; Arking, D E; Sotoodehnia, N PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity Journal Article Nat Commun, 9 (1), pp. 2904, 2018, ([PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060178PMC6060178] [DOI:hrefhttps://dx.doi.org/10.1038/s41467-018-04766-910.1038/s41467-018-04766-9] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2503542025035420]). @article{pmid30046033, title = {PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity}, author = {J van Setten and J A Brody and Y Jamshidi and B R Swenson and A M Butler and H Campbell and F M Del Greco and D S Evans and Q Gibson and D F Gudbjartsson and K F Kerr and B P Krijthe and L P Lyytikainen and C Muller and M Muller-Nurasyid and I M Nolte and S Padmanabhan and M D Ritchie and A Robino and A V Smith and M Steri and T Tanaka and A Teumer and S Trompet and S Ulivi and N Verweij and X Yin and D O Arnar and F W Asselbergs and J S Bader and J Barnard and J Bis and S Blankenberg and E Boerwinkle and Y Bradford and B M Buckley and M K Chung and D Crawford and M den Hoed and J C Denny and A F Dominiczak and G B Ehret and M Eijgelsheim and P T Ellinor and S B Felix and O H Franco and L Franke and T B Harris and H Holm and G Ilaria and A Iorio and M Kahonen and I Kolcic and J A Kors and E G Lakatta and L J Launer and H Lin and H J Lin and R J F Loos and S A Lubitz and P W Macfarlane and J W Magnani and I M Leach and T Meitinger and B D Mitchell and T Munzel and G J Papanicolaou and A Peters and A Pfeufer and P P Pramstaller and O T Raitakari and J I Rotter and I Rudan and N J Samani and D Schlessinger and C T Silva Aldana and M F Sinner and J D Smith and H Snieder and E Z Soliman and T D Spector and D J Stott and K Strauch and K V Tarasov and U Thorsteinsdottir and A G Uitterlinden and D R Van Wagoner and U Volker and H Volzke and M Waldenberger and H Jan Westra and P S Wild and T Zeller and A Alonso and C L Avery and S Bandinelli and E J Benjamin and F Cucca and M Dorr and L Ferrucci and P Gasparini and V Gudnason and C Hayward and S R Heckbert and A A Hicks and J W Jukema and S Kaab and T Lehtimaki and Y Liu and P B Munroe and A Parsa and O Polasek and B M Psaty and D M Roden and R B Schnabel and G Sinagra and K Stefansson and B H Stricker and P van der Harst and C M van Duijn and J F Wilson and S A Gharib and P I W de Bakker and A Isaacs and D E Arking and N Sotoodehnia}, year = {2018}, date = {2018-01-01}, journal = {Nat Commun}, volume = {9}, number = {1}, pages = {2904}, abstract = {Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.}, note = {[PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060178PMC6060178] [DOI:hrefhttps://dx.doi.org/10.1038/s41467-018-04766-910.1038/s41467-018-04766-9] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2503542025035420]}, keywords = {}, pubstate = {published}, tppubtype = {article} } Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development. |
Lee, J J; Wedow, R; Okbay, A; Kong, E; Maghzian, O; Zacher, M; Nguyen-Viet, T A; Bowers, P; Sidorenko, J; Linner, Karlsson R; Fontana, M A; Kundu, T; Lee, C; Li, H; Li, R; Royer, R; Timshel, P N; Walters, R K; Willoughby, E A; Yengo, L; Alver, M; Bao, Y; Clark, D W; Day, F R; Furlotte, N A; Joshi, P K; Kemper, K E; Kleinman, A; Langenberg, C; Magi, R; Trampush, J W; Verma, S S; Wu, Y; Lam, M; Zhao, J H; Zheng, Z; Boardman, J D; Campbell, H; Freese, J; Harris, K M; [...], ; Cucca, F; Cusi, D; Deary, I J; Dedoussis, G V; van Duijn, C M; Eriksson, J G; Franke, B; Franke, L; Gasparini, P; Gejman, P V; Gieger, C; Grabe, H J; Gratten, J; Groenen, P J F; Gudnason, V; van der Harst, P; Hayward, C; Hinds, D A; Hoffmann, W; Hypponen, E; Iacono, W G; Jacobsson, B; Jarvelin, M R; Jockel, K H; Kaprio, J; Kardia, S L R; Lehtimaki, T; Lehrer, S F; Magnusson, P K E; Martin, N G; McGue, M; Metspalu, A; Pendleton, N; Penninx, B W J H; Perola, M; Pirastu, N; Pirastu, M; Polasek, O; Posthuma, D; Power, C; Province, M A; Samani, N J; Schlessinger, D; Schmidt, R; S?rensen, T I A; Spector, T D; Stefansson, K; Thorsteinsdottir, U; Thurik, A R; Timpson, N J; Tiemeier, H; Tung, J Y; Uitterlinden, A G; Vitart, V; Vollenweider, P; Weir, D R; Wilson, J F; Wright, A F; Conley, D C; Krueger, R F; Smith, G D; Hofman, A; Laibson, D I; Medland, S E; Meyer, M N; Yang, J; Johannesson, M; Visscher, P M; Esko, T; Koellinger, P D; Cesarini, D; Benjamin, D J Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals Journal Article Nat. Genet., 50 (8), pp. 1112–1121, 2018, ([DOI:hrefhttps://dx.doi.org/10.1038/s41588-018-0147-310.1038/s41588-018-0147-3] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3003839630038396]). @article{pmid30038396, title = {Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals}, author = {J J Lee and R Wedow and A Okbay and E Kong and O Maghzian and M Zacher and T A Nguyen-Viet and P Bowers and J Sidorenko and R Karlsson Linner and M A Fontana and T Kundu and C Lee and H Li and R Li and R Royer and P N Timshel and R K Walters and E A Willoughby and L Yengo and M Alver and Y Bao and D W Clark and F R Day and N A Furlotte and P K Joshi and K E Kemper and A Kleinman and C Langenberg and R Magi and J W Trampush and S S Verma and Y Wu and M Lam and J H Zhao and Z Zheng and J D Boardman and H Campbell and J Freese and K M Harris and [...] and F Cucca and D Cusi and I J Deary and G V Dedoussis and C M van Duijn and J G Eriksson and B Franke and L Franke and P Gasparini and P V Gejman and C Gieger and H J Grabe and J Gratten and P J F Groenen and V Gudnason and P van der Harst and C Hayward and D A Hinds and W Hoffmann and E Hypponen and W G Iacono and B Jacobsson and M R Jarvelin and K H Jockel and J Kaprio and S L R Kardia and T Lehtimaki and S F Lehrer and P K E Magnusson and N G Martin and M McGue and A Metspalu and N Pendleton and B W J H Penninx and M Perola and N Pirastu and M Pirastu and O Polasek and D Posthuma and C Power and M A Province and N J Samani and D Schlessinger and R Schmidt and T I A S?rensen and T D Spector and K Stefansson and U Thorsteinsdottir and A R Thurik and N J Timpson and H Tiemeier and J Y Tung and A G Uitterlinden and V Vitart and P Vollenweider and D R Weir and J F Wilson and A F Wright and D C Conley and R F Krueger and G D Smith and A Hofman and D I Laibson and S E Medland and M N Meyer and J Yang and M Johannesson and P M Visscher and T Esko and P D Koellinger and D Cesarini and D J Benjamin}, year = {2018}, date = {2018-01-01}, journal = {Nat. Genet.}, volume = {50}, number = {8}, pages = {1112--1121}, abstract = {Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.}, note = {[DOI:hrefhttps://dx.doi.org/10.1038/s41588-018-0147-310.1038/s41588-018-0147-3] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3003839630038396]}, keywords = {}, pubstate = {published}, tppubtype = {article} } Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research. |
Yani, Lukas S; Keller, M; Melzer, F L; Weinberger, B; Pangrazzi, L; Sopper, S; Trieb, K; Lobina, M; Orru, V; Fiorillo, E; Cucca, F; Grubeck-Loebenstein, B CD8(+) HLADR(+) Regulatory T Cells Change With Aging: They Increase in Number, but Lose Checkpoint Inhibitory Molecules and Suppressive Function. Journal Article Front Immunol, 9 , pp. 1201, 2018, ([PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994398PMC5994398] [DOI:hrefhttps://dx.doi.org/10.3389/fimmu.2018.0120110.3389/fimmu.2018.01201] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2124352021243520]). @article{pmid29915580, title = {CD8(+) HLADR(+) Regulatory T Cells Change With Aging: They Increase in Number, but Lose Checkpoint Inhibitory Molecules and Suppressive Function. }, author = {S Lukas Yani and M Keller and F L Melzer and B Weinberger and L Pangrazzi and S Sopper and K Trieb and M Lobina and V Orru and E Fiorillo and F Cucca and B Grubeck-Loebenstein}, year = {2018}, date = {2018-01-01}, journal = {Front Immunol}, volume = {9}, pages = {1201}, abstract = {CD4+ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8+human leukocyte antigen-antigen D related (HLADR)+ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8+HLADR+ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8+HLADR+ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR- counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8+HLADR+ T cells from elderly persons are analyzed. In accordance with this finding, CD8+HLADR+ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8+ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as "inflamm-aging."}, note = {[PubMed Central:hrefhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994398PMC5994398] [DOI:hrefhttps://dx.doi.org/10.3389/fimmu.2018.0120110.3389/fimmu.2018.01201] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2124352021243520]}, keywords = {}, pubstate = {published}, tppubtype = {article} } CD4+ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8+human leukocyte antigen-antigen D related (HLADR)+ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8+HLADR+ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8+HLADR+ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR- counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8+HLADR+ T cells from elderly persons are analyzed. In accordance with this finding, CD8+HLADR+ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8+ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as "inflamm-aging." |
Piras, D; Masala, M; Delitala, A; Urru, S A M; Curreli, N; Balaci, L; Ferreli, L P; Loi, F; Atzeni, A; Cabiddu, G; Racugno, W; Ventura, L; Zoledziewska, M; Steri, M; Fiorillo, E; Pilia, M G; Schlessinger, D; Cucca, F; Rule, A D; Pani, A Kidney size in relation to ageing, gender, renal function, birthweight and chronic kidney disease risk factors in a general population Journal Article Nephrol. Dial. Transplant., 2018, ([DOI:hrefhttps://dx.doi.org/10.1093/ndt/gfy27010.1093/ndt/gfy270] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3016983330169833]). @article{pmid30169833, title = {Kidney size in relation to ageing, gender, renal function, birthweight and chronic kidney disease risk factors in a general population}, author = {D Piras and M Masala and A Delitala and S A M Urru and N Curreli and L Balaci and L P Ferreli and F Loi and A Atzeni and G Cabiddu and W Racugno and L Ventura and M Zoledziewska and M Steri and E Fiorillo and M G Pilia and D Schlessinger and F Cucca and A D Rule and A Pani}, year = {2018}, date = {2018-01-01}, journal = {Nephrol. Dial. Transplant.}, abstract = {The relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood. Ultrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18-100 years). We then identified the subset of 2256 'healthy' subjects to define age- and sex-specific reference ranges (2.5-97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys. In the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight. Overall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors.}, note = {[DOI:hrefhttps://dx.doi.org/10.1093/ndt/gfy27010.1093/ndt/gfy270] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3016983330169833]}, keywords = {}, pubstate = {published}, tppubtype = {article} } The relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood. Ultrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18-100 years). We then identified the subset of 2256 'healthy' subjects to define age- and sex-specific reference ranges (2.5-97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys. In the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight. Overall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors. |
2017 |
Piras, Doloretta ; Zoledziewska, Magdalena ; Cucca, Francesco ; Pani, Antonello Genome-Wide Analysis Studies and Chronic Kidney Disease. Journal Article Kidney Dis (Basel), 3 (3), pp. 106–110, 2017, ISSN: 2296-9381 2296-9357. @article{piras_genome-wide_2017, title = {Genome-Wide Analysis Studies and Chronic Kidney Disease.}, author = {Piras, Doloretta and Zoledziewska, Magdalena and Cucca, Francesco and Pani, Antonello}, doi = {10.1159/000481886}, issn = {2296-9381 2296-9357}, year = {2017}, date = {2017-12-01}, journal = {Kidney Dis (Basel)}, volume = {3}, number = {3}, pages = {106--110}, abstract = {In recent years, the very high worldwide prevalence of chronic kidney disease (CKD) has led some authors to talk of an "epidemic." The progression of CKD varies considerably among individuals despite similar aetiologies, optimal blood pressure, and glycaemic control. Over the last decade, through genome-wide association studies (GWAS), more than 50 genetic loci have been identified in association with CKD. Understanding the genetic basis of CKD could provide a better knowledge of the biology of the involved pathways, thus potentially leading to novel tools for the diagnosis, prevention, and therapy of CKD. In this review, we will analyse the role of GWAS in the study of CKD.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In recent years, the very high worldwide prevalence of chronic kidney disease (CKD) has led some authors to talk of an "epidemic." The progression of CKD varies considerably among individuals despite similar aetiologies, optimal blood pressure, and glycaemic control. Over the last decade, through genome-wide association studies (GWAS), more than 50 genetic loci have been identified in association with CKD. Understanding the genetic basis of CKD could provide a better knowledge of the biology of the involved pathways, thus potentially leading to novel tools for the diagnosis, prevention, and therapy of CKD. In this review, we will analyse the role of GWAS in the study of CKD. |
Iuculano, Ambra ; Stagnati, Valentina ; Serrenti, Marianna ; Peddes, Cristina ; Monni, Giovanni ; Sole, Gabriella ; Cucca, Francesco Crown-rump length: are they different or similar after homologous vs heterologous oocyte/embryo donation? Journal Article Am J Obstet Gynecol, 217 (2), pp. 224–225, 2017, ISSN: 1097-6868 0002-9378. @article{iuculano_crown-rump_2017b, title = {Crown-rump length: are they different or similar after homologous vs heterologous oocyte/embryo donation?}, author = {Iuculano, Ambra and Stagnati, Valentina and Serrenti, Marianna and Peddes, Cristina and Monni, Giovanni and Sole, Gabriella and Cucca, Francesco}, doi = {10.1016/j.ajog.2017.05.031}, issn = {1097-6868 0002-9378}, year = {2017}, date = {2017-08-01}, journal = {Am J Obstet Gynecol}, volume = {217}, number = {2}, pages = {224--225}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Boger, Carsten A; Gorski, Mathias ; McMahon, Gearoid M; Xu, Huichun ; Chang, Yen-Pei C; van der Most, Peter J; Navis, Gerjan ; Nolte, Ilja M; de Borst, Martin H; Zhang, Weihua ; Lehne, Benjamin ; Loh, Marie ; Tan, Sian-Tsung ; Boerwinkle, Eric ; Grams, Morgan E; Sekula, Peggy ; Li, Man ; Wilmot, Beth ; Moon, James G; Scheet, Paul ; Cucca, Francesco ; Xiao, Xiangjun ; Lyytikainen, Leo-Pekka ; Delgado, Graciela ; Grammer, Tanja B; Kleber, Marcus E; Sedaghat, Sanaz ; Rivadeneira, Fernando ; Corre, Tanguy ; Kutalik, Zoltan ; Bergmann, Sven ; Nielson, Carrie M; Srikanth, Priya ; Teumer, Alexander ; Muller-Nurasyid, Martina ; Brockhaus, Anne Catharina ; Pfeufer, Arne ; Rathmann, Wolfgang ; Peters, Annette ; Matsumoto, Martha ; de Andrade, Mariza ; Atkinson, Elizabeth J; Robinson-Cohen, Cassianne ; de Boer, Ian H; Hwang, Shih-Jen ; Heid, Iris M; Gogele, Martin ; Concas, Maria Pina ; Tanaka, Toshiko ; Bandinelli, Stefania ; Nalls, Mike A; Singleton, Andrew ; Tajuddin, Salman M; Adeyemo, Adebowale ; Zhou, Jie ; Doumatey, Ayo ; McWeeney, Shannon ; Murabito, Joanne ; Franceschini, Nora ; Flessner, Michael ; Shlipak, Michael ; Wilson, James G; Chen, Guanjie ; Rotimi, Charles N; Zonderman, Alan B; Evans, Michele K; Ferrucci, Luigi ; Devuyst, Olivier ; Pirastu, Mario ; Shuldiner, Alan ; Hicks, Andrew A; Pramstaller, Peter Paul ; Kestenbaum, Bryan ; Kardia, Sharon L R; Turner, Stephen T; Study, LifeLines Cohort ; Briske, Tamara Ellefson ; Gieger, Christian ; Strauch, Konstantin ; Meisinger, Christa ; Meitinger, Thomas ; Volker, Uwe ; Nauck, Matthias ; Volzke, Henry ; Vollenweider, Peter ; Bochud, Murielle ; Waeber, Gerard ; Kahonen, Mika ; Lehtimaki, Terho ; Marz, Winfried ; Dehghan, Abbas ; Franco, Oscar H; Uitterlinden, Andre G; Hofman, Albert ; Taylor, Herman A; Chambers, John C; Kooner, Jaspal S; Fox, Caroline S; Hitzemann, Robert ; Orwoll, Eric S; Pattaro, Cristian ; Schlessinger, David ; Kottgen, Anna ; Snieder, Harold ; Parsa, Afshin ; Cohen, David M NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality. Journal Article J Am Soc Nephrol, 28 (8), pp. 2311–2321, 2017, ISSN: 1533-3450 1046-6673. @article{boger_nfat5_2017, title = {NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.}, author = {Boger, Carsten A. and Gorski, Mathias and McMahon, Gearoid M. and Xu, Huichun and Chang, Yen-Pei C. and van der Most, Peter J. and Navis, Gerjan and Nolte, Ilja M. and de Borst, Martin H. and Zhang, Weihua and Lehne, Benjamin and Loh, Marie and Tan, Sian-Tsung and Boerwinkle, Eric and Grams, Morgan E. and Sekula, Peggy and Li, Man and Wilmot, Beth and Moon, James G. and Scheet, Paul and Cucca, Francesco and Xiao, Xiangjun and Lyytikainen, Leo-Pekka and Delgado, Graciela and Grammer, Tanja B. and Kleber, Marcus E. and Sedaghat, Sanaz and Rivadeneira, Fernando and Corre, Tanguy and Kutalik, Zoltan and Bergmann, Sven and Nielson, Carrie M. and Srikanth, Priya and Teumer, Alexander and Muller-Nurasyid, Martina and Brockhaus, Anne Catharina and Pfeufer, Arne and Rathmann, Wolfgang and Peters, Annette and Matsumoto, Martha and de Andrade, Mariza and Atkinson, Elizabeth J. and Robinson-Cohen, Cassianne and de Boer, Ian H. and Hwang, Shih-Jen and Heid, Iris M. and Gogele, Martin and Concas, Maria Pina and Tanaka, Toshiko and Bandinelli, Stefania and Nalls, Mike A. and Singleton, Andrew and Tajuddin, Salman M. and Adeyemo, Adebowale and Zhou, Jie and Doumatey, Ayo and McWeeney, Shannon and Murabito, Joanne and Franceschini, Nora and Flessner, Michael and Shlipak, Michael and Wilson, James G. and Chen, Guanjie and Rotimi, Charles N. and Zonderman, Alan B. and Evans, Michele K. and Ferrucci, Luigi and Devuyst, Olivier and Pirastu, Mario and Shuldiner, Alan and Hicks, Andrew A. and Pramstaller, Peter Paul and Kestenbaum, Bryan and Kardia, Sharon L. R. and Turner, Stephen T. and Study, LifeLines Cohort and Briske, Tamara Ellefson and Gieger, Christian and Strauch, Konstantin and Meisinger, Christa and Meitinger, Thomas and Volker, Uwe and Nauck, Matthias and Volzke, Henry and Vollenweider, Peter and Bochud, Murielle and Waeber, Gerard and Kahonen, Mika and Lehtimaki, Terho and Marz, Winfried and Dehghan, Abbas and Franco, Oscar H. and Uitterlinden, Andre G. and Hofman, Albert and Taylor, Herman A. and Chambers, John C. and Kooner, Jaspal S. and Fox, Caroline S. and Hitzemann, Robert and Orwoll, Eric S. and Pattaro, Cristian and Schlessinger, David and Kottgen, Anna and Snieder, Harold and Parsa, Afshin and Cohen, David M.}, doi = {10.1681/ASN.2016080892}, issn = {1533-3450 1046-6673}, year = {2017}, date = {2017-08-01}, journal = {J Am Soc Nephrol}, volume = {28}, number = {8}, pages = {2311--2321}, abstract = {Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at Ptextless5.0 x 10(-6) Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 x 10(-5)), with combined stages 1 and 2 genome-wide significance of P=5.6 x 10(-10) Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10(-12)). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10(-8)). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at Ptextless5.0 x 10(-6) Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 x 10(-5)), with combined stages 1 and 2 genome-wide significance of P=5.6 x 10(-10) Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10(-12)). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10(-8)). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance. |
Tanca, Alessandro ; Abbondio, Marcello ; Palomba, Antonio ; Fraumene, Cristina ; Manghina, Valeria ; Cucca, Francesco ; Fiorillo, Edoardo ; Uzzau, Sergio Potential and active functions in the gut microbiota of a healthy human cohort. Journal Article Microbiome, 5 (1), pp. 79, 2017, ISSN: 2049-2618 2049-2618. @article{tanca_potential_2017, title = {Potential and active functions in the gut microbiota of a healthy human cohort.}, author = {Tanca, Alessandro and Abbondio, Marcello and Palomba, Antonio and Fraumene, Cristina and Manghina, Valeria and Cucca, Francesco and Fiorillo, Edoardo and Uzzau, Sergio}, doi = {10.1186/s40168-017-0293-3}, issn = {2049-2618 2049-2618}, year = {2017}, date = {2017-07-01}, journal = {Microbiome}, volume = {5}, number = {1}, pages = {79}, abstract = {BACKGROUND: The study of the gut microbiota (GM) is rapidly moving towards its functional characterization by means of shotgun meta-omics. In this context, there is still no consensus on which microbial functions are consistently and constitutively expressed in the human gut in physiological conditions. Here, we selected a cohort of 15 healthy subjects from a native and highly monitored Sardinian population and analyzed their GMs using shotgun metaproteomics, with the aim of investigating GM functions actually expressed in a healthy human population. In addition, shotgun metagenomics was employed to reveal GM functional potential and to compare metagenome and metaproteome profiles in a combined taxonomic and functional fashion. RESULTS: Metagenomic and metaproteomic data concerning the taxonomic structure of the GM under study were globally comparable. On the contrary, a considerable divergence between genetic potential and functional activity of the human healthy GM was observed, with the metaproteome displaying a higher plasticity, compared to the lower inter-individual variability of metagenome profiles. The taxon-specific contribution to functional activities and metabolic tasks was also examined, giving insights into the peculiar role of several GM members in carbohydrate metabolism (including polysaccharide degradation, glycan transport, glycolysis, and short-chain fatty acid production). Noteworthy, Firmicutes-driven butyrogenesis (mainly due to Faecalibacterium spp.) was shown to be the metabolic activity with the highest expression rate and the lowest inter-individual variability in the study cohort, in line with the previously reported importance of the biosynthesis of this microbial product for the gut homeostasis. CONCLUSIONS: Our results provide detailed and taxon-specific information regarding functions and pathways actively working in a healthy GM. The reported discrepancy between expressed functions and functional potential suggests that caution should be used before drawing functional conclusions from metagenomic data, further supporting metaproteomics as a fundamental approach to characterize the human GM metabolic functions and activities.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: The study of the gut microbiota (GM) is rapidly moving towards its functional characterization by means of shotgun meta-omics. In this context, there is still no consensus on which microbial functions are consistently and constitutively expressed in the human gut in physiological conditions. Here, we selected a cohort of 15 healthy subjects from a native and highly monitored Sardinian population and analyzed their GMs using shotgun metaproteomics, with the aim of investigating GM functions actually expressed in a healthy human population. In addition, shotgun metagenomics was employed to reveal GM functional potential and to compare metagenome and metaproteome profiles in a combined taxonomic and functional fashion. RESULTS: Metagenomic and metaproteomic data concerning the taxonomic structure of the GM under study were globally comparable. On the contrary, a considerable divergence between genetic potential and functional activity of the human healthy GM was observed, with the metaproteome displaying a higher plasticity, compared to the lower inter-individual variability of metagenome profiles. The taxon-specific contribution to functional activities and metabolic tasks was also examined, giving insights into the peculiar role of several GM members in carbohydrate metabolism (including polysaccharide degradation, glycan transport, glycolysis, and short-chain fatty acid production). Noteworthy, Firmicutes-driven butyrogenesis (mainly due to Faecalibacterium spp.) was shown to be the metabolic activity with the highest expression rate and the lowest inter-individual variability in the study cohort, in line with the previously reported importance of the biosynthesis of this microbial product for the gut homeostasis. CONCLUSIONS: Our results provide detailed and taxon-specific information regarding functions and pathways actively working in a healthy GM. The reported discrepancy between expressed functions and functional potential suggests that caution should be used before drawing functional conclusions from metagenomic data, further supporting metaproteomics as a fundamental approach to characterize the human GM metabolic functions and activities. |
Tachmazidou, Ioanna ; Suveges, Daniel ; Min, Josine L; Ritchie, Graham R S; Steinberg, Julia ; Walter, Klaudia ; Iotchkova, Valentina ; Schwartzentruber, Jeremy ; Huang, Jie ; Memari, Yasin ; McCarthy, Shane ; Crawford, Andrew A; Bombieri, Cristina ; Cocca, Massimiliano ; Farmaki, Aliki-Eleni ; Gaunt, Tom R; Jousilahti, Pekka ; Kooijman, Marjolein N; Lehne, Benjamin ; Malerba, Giovanni ; Mannisto, Satu ; Matchan, Angela ; Medina-Gomez, Carolina ; Metrustry, Sarah J; Nag, Abhishek ; Ntalla, Ioanna ; Paternoster, Lavinia ; Rayner, Nigel W; Sala, Cinzia ; Scott, William R; Shihab, Hashem A; Southam, Lorraine ; St Pourcain, Beate ; Traglia, Michela ; Trajanoska, Katerina ; Zaza, Gialuigi ; Zhang, Weihua ; Artigas, Maria S; Bansal, Narinder ; Benn, Marianne ; Chen, Zhongsheng ; Danecek, Petr ; Lin, Wei-Yu ; Locke, Adam ; Luan, Jian'an ; Manning, Alisa K; Mulas, Antonella ; Sidore, Carlo ; Tybjaerg-Hansen, Anne ; Varbo, Anette ; Zoledziewska, Magdalena ; Finan, Chris ; Hatzikotoulas, Konstantinos ; Hendricks, Audrey E; Kemp, John P; Moayyeri, Alireza ; Panoutsopoulou, Kalliope ; Szpak, Michal ; Wilson, Scott G; Boehnke, Michael ; Cucca, Francesco ; Di Angelantonio, Emanuele ; Langenberg, Claudia ; Lindgren, Cecilia ; McCarthy, Mark I; Morris, Andrew P; Nordestgaard, Borge G; Scott, Robert A; Tobin, Martin D; Wareham, Nicholas J; Burton, Paul ; Chambers, John C; Smith, George Davey ; Dedoussis, George ; Felix, Janine F; Franco, Oscar H; Gambaro, Giovanni ; Gasparini, Paolo ; Hammond, Christopher J; Hofman, Albert ; Jaddoe, Vincent W V; Kleber, Marcus ; Kooner, Jaspal S; Perola, Markus ; Relton, Caroline ; Ring, Susan M; Rivadeneira, Fernando ; Salomaa, Veikko ; Spector, Timothy D; Stegle, Oliver ; Toniolo, Daniela ; Uitterlinden, Andre G; Barroso, Ines ; Greenwood, Celia M T; Perry, John R B; Walker, Brian R; Butterworth, Adam S; Xue, Yali ; Durbin, Richard ; Small, Kerrin S; Soranzo, Nicole ; Timpson, Nicholas J; Zeggini, Eleftheria Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. Journal Article Am J Hum Genet, 100 (6), pp. 865–884, 2017, ISSN: 1537-6605 0002-9297. @article{tachmazidou_whole-genome_2017, title = {Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.}, author = {Tachmazidou, Ioanna and Suveges, Daniel and Min, Josine L. and Ritchie, Graham R. S. and Steinberg, Julia and Walter, Klaudia and Iotchkova, Valentina and Schwartzentruber, Jeremy and Huang, Jie and Memari, Yasin and McCarthy, Shane and Crawford, Andrew A. and Bombieri, Cristina and Cocca, Massimiliano and Farmaki, Aliki-Eleni and Gaunt, Tom R. and Jousilahti, Pekka and Kooijman, Marjolein N. and Lehne, Benjamin and Malerba, Giovanni and Mannisto, Satu and Matchan, Angela and Medina-Gomez, Carolina and Metrustry, Sarah J. and Nag, Abhishek and Ntalla, Ioanna and Paternoster, Lavinia and Rayner, Nigel W. and Sala, Cinzia and Scott, William R. and Shihab, Hashem A. and Southam, Lorraine and St Pourcain, Beate and Traglia, Michela and Trajanoska, Katerina and Zaza, Gialuigi and Zhang, Weihua and Artigas, Maria S. and Bansal, Narinder and Benn, Marianne and Chen, Zhongsheng and Danecek, Petr and Lin, Wei-Yu and Locke, Adam and Luan, Jian'an and Manning, Alisa K. and Mulas, Antonella and Sidore, Carlo and Tybjaerg-Hansen, Anne and Varbo, Anette and Zoledziewska, Magdalena and Finan, Chris and Hatzikotoulas, Konstantinos and Hendricks, Audrey E. and Kemp, John P. and Moayyeri, Alireza and Panoutsopoulou, Kalliope and Szpak, Michal and Wilson, Scott G. and Boehnke, Michael and Cucca, Francesco and Di Angelantonio, Emanuele and Langenberg, Claudia and Lindgren, Cecilia and McCarthy, Mark I. and Morris, Andrew P. and Nordestgaard, Borge G. and Scott, Robert A. and Tobin, Martin D. and Wareham, Nicholas J. and Burton, Paul and Chambers, John C. and Smith, George Davey and Dedoussis, George and Felix, Janine F. and Franco, Oscar H. and Gambaro, Giovanni and Gasparini, Paolo and Hammond, Christopher J. and Hofman, Albert and Jaddoe, Vincent W. V. and Kleber, Marcus and Kooner, Jaspal S. and Perola, Markus and Relton, Caroline and Ring, Susan M. and Rivadeneira, Fernando and Salomaa, Veikko and Spector, Timothy D. and Stegle, Oliver and Toniolo, Daniela and Uitterlinden, Andre G. and Barroso, Ines and Greenwood, Celia M. T. and Perry, John R. B. and Walker, Brian R. and Butterworth, Adam S. and Xue, Yali and Durbin, Richard and Small, Kerrin S. and Soranzo, Nicole and Timpson, Nicholas J. and Zeggini, Eleftheria}, doi = {10.1016/j.ajhg.2017.04.014}, issn = {1537-6605 0002-9297}, year = {2017}, date = {2017-06-01}, journal = {Am J Hum Genet}, volume = {100}, number = {6}, pages = {865--884}, abstract = {Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum. |
Iuculano, Ambra; Stagnati, Valentina; Serrenti, Marianna; Peddes, Cristina; Monni, Giovanni; Sole, Gabriella; Cucca, Francesco Crown-rump length: are they different or similar after homologous vs heterologous oocyte/embryo donation? Journal Article American Journal of Obstetrics and Gynecology, 2017, ISSN: 1097-6868. @article{iuculano_crown-rump_2017, title = {Crown-rump length: are they different or similar after homologous vs heterologous oocyte/embryo donation?}, author = {Ambra Iuculano and Valentina Stagnati and Marianna Serrenti and Cristina Peddes and Giovanni Monni and Gabriella Sole and Francesco Cucca}, doi = {10.1016/j.ajog.2017.05.031}, issn = {1097-6868}, year = {2017}, date = {2017-05-01}, journal = {American Journal of Obstetrics and Gynecology}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Qian, Yong ; Butler, Thomas J; Opsahl-Ong, Krista ; Giroux, Nicholas S; Sidore, Carlo ; Nagaraja, Ramaiah ; Cucca, Francesco ; Ferrucci, Luigi ; Abecasis, Goncalo R; Schlessinger, David ; Ding, Jun fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences. Journal Article Bioinformatics, 33 (9), pp. 1399–1401, 2017, ISSN: 1367-4811 1367-4803. @article{qian_fastmitocalc:_2017, title = {fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences.}, author = {Qian, Yong and Butler, Thomas J. and Opsahl-Ong, Krista and Giroux, Nicholas S. and Sidore, Carlo and Nagaraja, Ramaiah and Cucca, Francesco and Ferrucci, Luigi and Abecasis, Goncalo R. and Schlessinger, David and Ding, Jun}, doi = {10.1093/bioinformatics/btw835}, issn = {1367-4811 1367-4803}, year = {2017}, date = {2017-05-01}, journal = {Bioinformatics}, volume = {33}, number = {9}, pages = {1399--1401}, abstract = {Availability and Implementation: fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html. Contact: jun.ding@nih.gov. Supplementary information: Supplementary data are available at Bioinformatics online.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Availability and Implementation: fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html. Contact: jun.ding@nih.gov. Supplementary information: Supplementary data are available at Bioinformatics online. |
Olivieri, Anna; Sidore, Carlo; Achilli, Alessandro; Angius, Andrea; Posth, Cosimo; ä, Anja Furtw; Brandini, Stefania; Capodiferro, Marco Rosario; Gandini, Francesca; Zoledziewska, Magdalena; Pitzalis, Maristella; Maschio, Andrea; Busonero, Fabio; Lai, Luca; Skeates, Robin; Gradoli, Maria Giuseppina; Beckett, Jessica; Marongiu, Michele; Mazzarello, Vittorio; Marongiu, Patrizia; Rubino, Salvatore; Rito, Teresa; Macaulay, Vincent; Semino, Ornella; Pala, Maria; ç, Gon; Schlessinger, David; Conde-Sousa, Eduardo; Soares, Pedro; Richards, Martin B; Cucca, Francesco; Torroni, Antonio Mitogenome Diversity in Sardinians: A Genetic Window onto an Island's Past Journal Article Molecular Biology and Evolution, 34 (5), pp. 1230–1239, 2017, ISSN: 1537-1719. @article{olivieri_mitogenome_2017, title = {Mitogenome Diversity in Sardinians: A Genetic Window onto an Island's Past}, author = {Anna Olivieri and Carlo Sidore and Alessandro Achilli and Andrea Angius and Cosimo Posth and Anja Furtw{ä}ngler and Stefania Brandini and Marco Rosario Capodiferro and Francesca Gandini and Magdalena Zoledziewska and Maristella Pitzalis and Andrea Maschio and Fabio Busonero and Luca Lai and Robin Skeates and Maria Giuseppina Gradoli and Jessica Beckett and Michele Marongiu and Vittorio Mazzarello and Patrizia Marongiu and Salvatore Rubino and Teresa Rito and Vincent Macaulay and Ornella Semino and Maria Pala and Gon{ç}alo R Abecasis and David Schlessinger and Eduardo Conde-Sousa and Pedro Soares and Martin B Richards and Francesco Cucca and Antonio Torroni}, doi = {10.1093/molbev/msx082}, issn = {1537-1719}, year = {2017}, date = {2017-05-01}, journal = {Molecular Biology and Evolution}, volume = {34}, number = {5}, pages = {1230--1239}, abstract = {Sardinians are öutliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Sardinians are öutliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia. |
Pala, Mauro; Zappala, Zachary; Marongiu, Mara; Li, Xin; Davis, Joe R; Cusano, Roberto; Crobu, Francesca; Kukurba, Kimberly R; Gloudemans, Michael J; Reinier, Frederic; Berutti, Riccardo; Piras, Maria G; Mulas, Antonella; Zoledziewska, Magdalena; Marongiu, Michele; Sorokin, Elena P; Hess, Gaelen T; Smith, Kevin S; Busonero, Fabio; Maschio, Andrea; Steri, Maristella; Sidore, Carlo; Sanna, Serena; Fiorillo, Edoardo; Bassik, Michael C; Sawcer, Stephen J; Battle, Alexis; Novembre, John; Jones, Chris; Angius, Andrea; ç, Gon; Schlessinger, David; Cucca, Francesco; Montgomery, Stephen B Population- and individual-specific regulatory variation in Sardinia Journal Article Nature Genetics, 49 (5), pp. 700–707, 2017, ISSN: 1546-1718. @article{pala_population-_2017, title = {Population- and individual-specific regulatory variation in Sardinia}, author = {Mauro Pala and Zachary Zappala and Mara Marongiu and Xin Li and Joe R Davis and Roberto Cusano and Francesca Crobu and Kimberly R Kukurba and Michael J Gloudemans and Frederic Reinier and Riccardo Berutti and Maria G Piras and Antonella Mulas and Magdalena Zoledziewska and Michele Marongiu and Elena P Sorokin and Gaelen T Hess and Kevin S Smith and Fabio Busonero and Andrea Maschio and Maristella Steri and Carlo Sidore and Serena Sanna and Edoardo Fiorillo and Michael C Bassik and Stephen J Sawcer and Alexis Battle and John Novembre and Chris Jones and Andrea Angius and Gon{ç}alo R Abecasis and David Schlessinger and Francesco Cucca and Stephen B Montgomery}, doi = {10.1038/ng.3840}, issn = {1546-1718}, year = {2017}, date = {2017-05-01}, journal = {Nature Genetics}, volume = {49}, number = {5}, pages = {700--707}, abstract = {Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk. |
Doro, Maria G; Casu, Giuseppina ; Frogheri, Laura ; Persico, Ivana ; Triet, Le Phan Minh ; Hoa, Phan Thi Thuy ; Hoang, Nguyen Huy ; Pirastru, Monica ; Mereu, Paolo ; Cucca, Francesco ; Masala, Bruno Molecular Characterization of beta-Thalassemia Mutations in Central Vietnam. Journal Article Hemoglobin, 41 (2), pp. 96–99, 2017, ISSN: 1532-432X 0363-0269. @article{doro_molecular_2017, title = {Molecular Characterization of beta-Thalassemia Mutations in Central Vietnam.}, author = {Doro, Maria G. and Casu, Giuseppina and Frogheri, Laura and Persico, Ivana and Triet, Le Phan Minh and Hoa, Phan Thi Thuy and Hoang, Nguyen Huy and Pirastru, Monica and Mereu, Paolo and Cucca, Francesco and Masala, Bruno}, doi = {10.1080/03630269.2017.1321013}, issn = {1532-432X 0363-0269}, year = {2017}, date = {2017-03-01}, journal = {Hemoglobin}, volume = {41}, number = {2}, pages = {96--99}, abstract = {The molecular basis of beta-thalassemia (beta-thal) mutations in North and in South Vietnam have been described during the past 15 years, whereas limited data were available concerning the central area of the country. In this study, we describe the molecular characterization and frequency of beta-globin gene mutations in the Thua Thien Hue Province of Central Vietnam as the result of a first survey conducted in 22 transfusion-dependent patients, and four unrelated heterozygotes. Nine different known mutations were identified (seven of the beta(0) and two of the beta(+) type) in a total of 48 chromosomes. The most common was codon 26 (GtextgreaterA) or Hb E (HBB: c.79 GtextgreaterA) accounting for 29.2% of the total studied chromosomes, followed by codon 17 (AtextgreaterT) (HBB: c.52 AtextgreaterT) (25.0%), and codons 41/42 (-TTCT) (HBB: c.126_129delCTTT) (18.8%). Other mutations with appreciable frequencies (6.3-8.3%) were IVS-I-1 (GtextgreaterT) (HBB: c.92+1 GtextgreaterT), codon 26 (GtextgreaterT) (HBB: c.79 GtextgreaterT) and codons 71/72 (+A) (HBB: c.216_217insA). Relatively rarer (2.0%) were the promoter -28 (AtextgreaterG) (HBB: c.78 AtextgreaterG) mutation, the codon 95 (+A) (HBB: c.287_288insA), which is reported only in the Vietnamese, and the codons 14/15 (+G) (HBB: c.45_46insG) mutation, thus far observed only in Thailand. Results are relevant for implementing appropriate measures for beta-thal prevention and control in the region as well as in the whole country.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The molecular basis of beta-thalassemia (beta-thal) mutations in North and in South Vietnam have been described during the past 15 years, whereas limited data were available concerning the central area of the country. In this study, we describe the molecular characterization and frequency of beta-globin gene mutations in the Thua Thien Hue Province of Central Vietnam as the result of a first survey conducted in 22 transfusion-dependent patients, and four unrelated heterozygotes. Nine different known mutations were identified (seven of the beta(0) and two of the beta(+) type) in a total of 48 chromosomes. The most common was codon 26 (GtextgreaterA) or Hb E (HBB: c.79 GtextgreaterA) accounting for 29.2% of the total studied chromosomes, followed by codon 17 (AtextgreaterT) (HBB: c.52 AtextgreaterT) (25.0%), and codons 41/42 (-TTCT) (HBB: c.126_129delCTTT) (18.8%). Other mutations with appreciable frequencies (6.3-8.3%) were IVS-I-1 (GtextgreaterT) (HBB: c.92+1 GtextgreaterT), codon 26 (GtextgreaterT) (HBB: c.79 GtextgreaterT) and codons 71/72 (+A) (HBB: c.216_217insA). Relatively rarer (2.0%) were the promoter -28 (AtextgreaterG) (HBB: c.78 AtextgreaterG) mutation, the codon 95 (+A) (HBB: c.287_288insA), which is reported only in the Vietnamese, and the codons 14/15 (+G) (HBB: c.45_46insG) mutation, thus far observed only in Thailand. Results are relevant for implementing appropriate measures for beta-thal prevention and control in the region as well as in the whole country. |
Palombo, Flavia ; Al-Wardy, Nadia ; Ruscone, Guido Alberto Gnecchi ; Oppo, Manuela ; Kindi, Mohammed Nasser Al ; Angius, Andrea ; Al Lamki, Khalsa ; Girotto, Giorgia ; Giangregorio, Tania ; Benelli, Matteo ; Magi, Alberto ; Seri, Marco ; Gasparini, Paolo ; Cucca, Francesco ; Sazzini, Marco ; Al Khabori, Mazin ; Pippucci, Tommaso ; Romeo, Giovanni A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman. Journal Article J Hum Genet, 62 (2), pp. 259–264, 2017, ISSN: 1435-232X 1434-5161. @article{palombo_novel_2017, title = {A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman.}, author = {Palombo, Flavia and Al-Wardy, Nadia and Ruscone, Guido Alberto Gnecchi and Oppo, Manuela and Kindi, Mohammed Nasser Al and Angius, Andrea and Al Lamki, Khalsa and Girotto, Giorgia and Giangregorio, Tania and Benelli, Matteo and Magi, Alberto and Seri, Marco and Gasparini, Paolo and Cucca, Francesco and Sazzini, Marco and Al Khabori, Mazin and Pippucci, Tommaso and Romeo, Giovanni}, doi = {10.1038/jhg.2016.120}, issn = {1435-232X 1434-5161}, year = {2017}, date = {2017-02-01}, journal = {J Hum Genet}, volume = {62}, number = {2}, pages = {259--264}, abstract = {The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman. |
de Vries, Paul S; Sabater-Lleal, Maria ; Chasman, Daniel I; Trompet, Stella ; Ahluwalia, Tarunveer S; Teumer, Alexander ; Kleber, Marcus E; Chen, Ming-Huei ; Wang, Jie Jin ; Attia, John R; Marioni, Riccardo E; Steri, Maristella ; Weng, Lu-Chen ; Pool, Rene ; Grossmann, Vera ; Brody, Jennifer A; Venturini, Cristina ; Tanaka, Toshiko ; Rose, Lynda M; Oldmeadow, Christopher ; Mazur, Johanna ; Basu, Saonli ; Franberg, Mattias ; Yang, Qiong ; Ligthart, Symen ; Hottenga, Jouke J; Rumley, Ann ; Mulas, Antonella ; de Craen, Anton J M; Grotevendt, Anne ; Taylor, Kent D; Delgado, Graciela E; Kifley, Annette ; Lopez, Lorna M; Berentzen, Tina L; Mangino, Massimo ; Bandinelli, Stefania ; Morrison, Alanna C; Hamsten, Anders ; Tofler, Geoffrey ; de Maat, Moniek P M; Draisma, Harmen H M; Lowe, Gordon D; Zoledziewska, Magdalena ; Sattar, Naveed ; Lackner, Karl J; Volker, Uwe ; McKnight, Barbara ; Huang, Jie ; Holliday, Elizabeth G; McEvoy, Mark A; Starr, John M; Hysi, Pirro G; Hernandez, Dena G; Guan, Weihua ; Rivadeneira, Fernando ; McArdle, Wendy L; Slagboom, Eline P; Zeller, Tanja ; Psaty, Bruce M; Uitterlinden, Andre G; de Geus, Eco J C; Stott, David J; Binder, Harald ; Hofman, Albert ; Franco, Oscar H; Rotter, Jerome I; Ferrucci, Luigi ; Spector, Tim D; Deary, Ian J; Marz, Winfried ; Greinacher, Andreas ; Wild, Philipp S; Cucca, Francesco ; Boomsma, Dorret I; Watkins, Hugh ; Tang, Weihong ; Ridker, Paul M; Jukema, Jan W; Scott, Rodney J; Mitchell, Paul ; Hansen, Torben ; O'Donnell, Christopher J; Smith, Nicholas L; Strachan, David P; Dehghan, Abbas Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. Journal Article PLoS One, 12 (1), pp. e0167742, 2017, ISSN: 1932-6203 1932-6203. @article{de_vries_comparison_2017, title = {Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.}, author = {de Vries, Paul S. and Sabater-Lleal, Maria and Chasman, Daniel I. and Trompet, Stella and Ahluwalia, Tarunveer S. and Teumer, Alexander and Kleber, Marcus E. and Chen, Ming-Huei and Wang, Jie Jin and Attia, John R. and Marioni, Riccardo E. and Steri, Maristella and Weng, Lu-Chen and Pool, Rene and Grossmann, Vera and Brody, Jennifer A. and Venturini, Cristina and Tanaka, Toshiko and Rose, Lynda M. and Oldmeadow, Christopher and Mazur, Johanna and Basu, Saonli and Franberg, Mattias and Yang, Qiong and Ligthart, Symen and Hottenga, Jouke J. and Rumley, Ann and Mulas, Antonella and de Craen, Anton J. M. and Grotevendt, Anne and Taylor, Kent D. and Delgado, Graciela E. and Kifley, Annette and Lopez, Lorna M. and Berentzen, Tina L. and Mangino, Massimo and Bandinelli, Stefania and Morrison, Alanna C. and Hamsten, Anders and Tofler, Geoffrey and de Maat, Moniek P. M. and Draisma, Harmen H. M. and Lowe, Gordon D. and Zoledziewska, Magdalena and Sattar, Naveed and Lackner, Karl J. and Volker, Uwe and McKnight, Barbara and Huang, Jie and Holliday, Elizabeth G. and McEvoy, Mark A. and Starr, John M. and Hysi, Pirro G. and Hernandez, Dena G. and Guan, Weihua and Rivadeneira, Fernando and McArdle, Wendy L. and Slagboom, P. Eline and Zeller, Tanja and Psaty, Bruce M. and Uitterlinden, Andre G. and de Geus, Eco J. C. and Stott, David J. and Binder, Harald and Hofman, Albert and Franco, Oscar H. and Rotter, Jerome I. and Ferrucci, Luigi and Spector, Tim D. and Deary, Ian J. and Marz, Winfried and Greinacher, Andreas and Wild, Philipp S. and Cucca, Francesco and Boomsma, Dorret I. and Watkins, Hugh and Tang, Weihong and Ridker, Paul M. and Jukema, Jan W. and Scott, Rodney J. and Mitchell, Paul and Hansen, Torben and O'Donnell, Christopher J. and Smith, Nicholas L. and Strachan, David P. and Dehghan, Abbas}, doi = {10.1371/journal.pone.0167742}, issn = {1932-6203 1932-6203}, year = {2017}, date = {2017-01-01}, journal = {PLoS One}, volume = {12}, number = {1}, pages = {e0167742}, abstract = {An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value textless 2.5x10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.}, keywords = {}, pubstate = {published}, tppubtype = {article} } An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value textless 2.5x10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development. |
Steri, Maristella; Orrù, Valeria; Idda, Laura M; Pitzalis, Maristella; Pala, Mauro; Zara, Ilenia; Sidore, Carlo; Faà, Valeria; Floris, Matteo; Deiana, Manila; Asunis, Isadora; Porcu, Eleonora; Mulas, Antonella; Piras, Maria G; Lobina, Monia; Lai, Sandra; Marongiu, Mara; Serra, Valentina; Marongiu, Michele; Sole, Gabriella; Busonero, Fabio; Maschio, Andrea; Cusano, Roberto; Cuccuru, Gianmauro; Deidda, Francesca; Poddie, Fausto; Farina, Gabriele; Dei, Mariano; Virdis, Francesca; Olla, Stefania; Satta, Maria A; Pani, Mario; Delitala, Alessandro; Cocco, Eleonora; Frau, Jessica; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Ferrigno, Paola; Ban, Maria; Barizzone, Nadia; Leone, Maurizio; Guerini, Franca R; Piga, Matteo; Firinu, Davide; Kockum, Ingrid; Lima Bomfim, Izaura ; Olsson, Tomas; Alfredsson, Lars; Suarez, Ana; Carreira, Patricia E; Castillo-Palma, Maria J; Marcus, Joseph H; Congia, Mauro; Angius, Andrea; Melis, Maurizio; Gonzalez, Antonio; ó}n Riquelme, Marta {Alarc E; da Silva, Berta M; Marchini, Maurizio; Danieli, Maria G; Del Giacco, Stefano ; Mathieu, Alessandro; Pani, Antonello; Montgomery, Stephen B; Rosati, Giulio; Hillert, Jan; Sawcer, Stephen; D'Alfonso, Sandra; Todd, John A; Novembre, John; ç, Gon; Whalen, Michael B; Marrosu, Maria G; Meloni, Alessandra; Sanna, Serena; Gorospe, Myriam; Schlessinger, David; Fiorillo, Edoardo; Zoledziewska, Magdalena; Cucca, Francesco Overexpression of the Cytokine BAFF and Autoimmunity Risk Journal Article The New England Journal of Medicine, 376 (17), pp. 1615–1626, 2017, ISSN: 1533-4406, (See Editorials, Korn T, Oukka M. A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis. N Engl J Med. 2017 Apr 27;376(17):1680-1681. doi: 10.1056/NEJMe1700720.; Stohl W., Systemic lupus erythematosus: BAFF emerges from the genetic shadows. Nat Rev Rheumatol. 2017 Jun 15. doi: 10.1038/nrrheum.2017.99; Comabella M. Neuroimmunology: B cells and variant BAFF in autoimmune disease. Nat Rev Neurol. 2017 Jun 16. doi: 10.1038/nrneurol.2017.87.). @article{steri_overexpression_2017, title = {Overexpression of the Cytokine BAFF and Autoimmunity Risk}, author = {Maristella Steri and Valeria Orrù and Laura M Idda and Maristella Pitzalis and Mauro Pala and Ilenia Zara and Carlo Sidore and Valeria Faà and Matteo Floris and Manila Deiana and Isadora Asunis and Eleonora Porcu and Antonella Mulas and Maria G Piras and Monia Lobina and Sandra Lai and Mara Marongiu and Valentina Serra and Michele Marongiu and Gabriella Sole and Fabio Busonero and Andrea Maschio and Roberto Cusano and Gianmauro Cuccuru and Francesca Deidda and Fausto Poddie and Gabriele Farina and Mariano Dei and Francesca Virdis and Stefania Olla and Maria A Satta and Mario Pani and Alessandro Delitala and Eleonora Cocco and Jessica Frau and Giancarlo Coghe and Lorena Lorefice and Giuseppe Fenu and Paola Ferrigno and Maria Ban and Nadia Barizzone and Maurizio Leone and Franca R Guerini and Matteo Piga and Davide Firinu and Ingrid Kockum and Izaura {Lima Bomfim} and Tomas Olsson and Lars Alfredsson and Ana Suarez and Patricia E Carreira and Maria J Castillo-Palma and Joseph H Marcus and Mauro Congia and Andrea Angius and Maurizio Melis and Antonio Gonzalez and Marta E {Alarc{ó}n Riquelme} and Berta M da Silva and Maurizio Marchini and Maria G Danieli and Stefano {Del Giacco} and Alessandro Mathieu and Antonello Pani and Stephen B Montgomery and Giulio Rosati and Jan Hillert and Stephen Sawcer and Sandra D'Alfonso and John A Todd and John Novembre and Gon{ç}alo R Abecasis and Michael B Whalen and Maria G Marrosu and Alessandra Meloni and Serena Sanna and Myriam Gorospe and David Schlessinger and Edoardo Fiorillo and Magdalena Zoledziewska and Francesco Cucca}, doi = {10.1056/NEJMoa1610528}, issn = {1533-4406}, year = {2017}, date = {2017-01-01}, journal = {The New England Journal of Medicine}, volume = {376}, number = {17}, pages = {1615--1626}, abstract = {BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).}, note = {See Editorials, Korn T, Oukka M. A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis. N Engl J Med. 2017 Apr 27;376(17):1680-1681. doi: 10.1056/NEJMe1700720.; Stohl W., Systemic lupus erythematosus: BAFF emerges from the genetic shadows. Nat Rev Rheumatol. 2017 Jun 15. doi: 10.1038/nrrheum.2017.99; Comabella M. Neuroimmunology: B cells and variant BAFF in autoimmune disease. Nat Rev Neurol. 2017 Jun 16. doi: 10.1038/nrneurol.2017.87.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.). |
2016 |
Scuteri, Angelo ; Franco, Oscar H; Majiid, AlGhatrif ; Jolita, Badariene ; Sergey, Boytsov ; Cheng, Hao-Min ; Chen, Chen-Huan ; Choi, Seong-Woo ; Francesco, Cucca ; De Buyzere, Marc L; Alessandro, Delitala ; Marcus, Dorr ; Gunnar, Engstrom ; Albert, Hofman ; Seul-Ki, Jeong ; Kweon, Sun-Seog ; Michel, Langlois ; Lee, Young-Hoon ; Mattace Raso, Francesco ; Olle, Melander ; Morrell, Cristopher H; Park, Kyeong-Soo ; Rietzschel, Ernst R; Kristina, Ryliskiene ; Ryliskyte, Ligita ; Ulf, Schminke ; David, Schlessinger ; Shin, Min-Ho ; Irina, Strazhesko ; Shih-Hsien, Sung ; Olga, Tkacheva ; Volzke, Henry ; Lakatta, Edward G; Nilsson, Peter The relationship between the metabolic syndrome and arterial wall thickness: A mosaic still to be interpreted. Journal Article Atherosclerosis, 255 , pp. 11–16, 2016, ISSN: 1879-1484 0021-9150. @article{scuteri_relationship_2016, title = {The relationship between the metabolic syndrome and arterial wall thickness: A mosaic still to be interpreted.}, author = {Scuteri, Angelo and Franco, Oscar H. and Majiid, AlGhatrif and Jolita, Badariene and Sergey, Boytsov and Cheng, Hao-Min and Chen, Chen-Huan and Choi, Seong-Woo and Francesco, Cucca and De Buyzere, Marc L. and Alessandro, Delitala and Marcus, Dorr and Gunnar, Engstrom and Albert, Hofman and Seul-Ki, Jeong and Kweon, Sun-Seog and Michel, Langlois and Lee, Young-Hoon and Mattace Raso, Francesco and Olle, Melander and Morrell, Cristopher H. and Park, Kyeong-Soo and Rietzschel, Ernst R. and Kristina, Ryliskiene and Ryliskyte, Ligita and Ulf, Schminke and David, Schlessinger and Shin, Min-Ho and Irina, Strazhesko and Shih-Hsien, Sung and Olga, Tkacheva and Volzke, Henry and Lakatta, Edward G. and Nilsson, Peter}, doi = {10.1016/j.atherosclerosis.2016.10.032}, issn = {1879-1484 0021-9150}, year = {2016}, date = {2016-12-01}, journal = {Atherosclerosis}, volume = {255}, pages = {11--16}, abstract = {BACKGROUND AND AIMS: We aimed to identify clusters of metabolic syndrome (MetS) components, risky for extremely high intima-media thickness. METHODS: We studied 41,513 volunteers (men and women) from eleven cohorts worldwide, participating in the MARE (Metabolic syndrome and Artery REsearch) Consortium. RESULTS: Specific clusters of MetS components - high triglycerides-high blood pressure-abdominal obesity (TBW), low HDL cholesterol-high blood pressure-abdominal obesity (HBW), high glucose-high blood pressure-abdominal obesity (GBW) - were accompanied by a}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND AND AIMS: We aimed to identify clusters of metabolic syndrome (MetS) components, risky for extremely high intima-media thickness. METHODS: We studied 41,513 volunteers (men and women) from eleven cohorts worldwide, participating in the MARE (Metabolic syndrome and Artery REsearch) Consortium. RESULTS: Specific clusters of MetS components - high triglycerides-high blood pressure-abdominal obesity (TBW), low HDL cholesterol-high blood pressure-abdominal obesity (HBW), high glucose-high blood pressure-abdominal obesity (GBW) - were accompanied by a |
Danjou, Fabrice ; Fozza, Claudio ; Zoledziewska, Magdalena ; Mulas, Antonella ; Corda, Giovanna ; Contini, Salvatore ; Dore, Fausto ; Galleu, Antonio ; Di Tucci, Anna Angela ; Caocci, Giovanni ; Gaviano, Eleonora ; Latte, Giancarlo ; Gabbas, Attilio ; Casula, Paolo ; Delogu, Lucia Gemma ; La Nasa, Giorgio ; Angelucci, Emanuele ; Cucca, Francesco ; Longinotti, Maurizio A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromes. Journal Article Exp Hematol, 44 (11), pp. 1034–1038, 2016, ISSN: 1873-2399 0301-472X. @article{danjou_genome-wide_2016, title = {A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromes.}, author = {Danjou, Fabrice and Fozza, Claudio and Zoledziewska, Magdalena and Mulas, Antonella and Corda, Giovanna and Contini, Salvatore and Dore, Fausto and Galleu, Antonio and Di Tucci, Anna Angela and Caocci, Giovanni and Gaviano, Eleonora and Latte, Giancarlo and Gabbas, Attilio and Casula, Paolo and Delogu, Lucia Gemma and La Nasa, Giorgio and Angelucci, Emanuele and Cucca, Francesco and Longinotti, Maurizio}, doi = {10.1016/j.exphem.2016.07.005}, issn = {1873-2399 0301-472X}, year = {2016}, date = {2016-11-01}, journal = {Exp Hematol}, volume = {44}, number = {11}, pages = {1034--1038}, abstract = {Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 (p = 1.16 x 10(-12)), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 x 10(-6) and 3.34 x 10(-6), are situated in the methylene tetrahydrofolate reductase (MTHFR) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 (p = 1.16 x 10(-12)), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 x 10(-6) and 3.34 x 10(-6), are situated in the methylene tetrahydrofolate reductase (MTHFR) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability. |
McCarthy, Shane ; Das, Sayantan ; Kretzschmar, Warren ; Delaneau, Olivier ; Wood, Andrew R; Teumer, Alexander ; Kang, Hyun Min ; Fuchsberger, Christian ; Danecek, Petr ; Sharp, Kevin ; Luo, Yang ; Sidore, Carlo ; Kwong, Alan ; Timpson, Nicholas ; Koskinen, Seppo ; Vrieze, Scott ; Scott, Laura J; Zhang, He ; Mahajan, Anubha ; Veldink, Jan ; Peters, Ulrike ; Pato, Carlos ; van Duijn, Cornelia M; Gillies, Christopher E; Gandin, Ilaria ; Mezzavilla, Massimo ; Gilly, Arthur ; Cocca, Massimiliano ; Traglia, Michela ; Angius, Andrea ; Barrett, Jeffrey C; Boomsma, Dorrett ; Branham, Kari ; Breen, Gerome ; Brummett, Chad M; Busonero, Fabio ; Campbell, Harry ; Chan, Andrew ; Chen, Sai ; Chew, Emily ; Collins, Francis S; Corbin, Laura J; Smith, George Davey ; Dedoussis, George ; Dorr, Marcus ; Farmaki, Aliki-Eleni ; Ferrucci, Luigi ; Forer, Lukas ; Fraser, Ross M; Gabriel, Stacey ; Levy, Shawn ; Groop, Leif ; Harrison, Tabitha ; Hattersley, Andrew ; Holmen, Oddgeir L; Hveem, Kristian ; Kretzler, Matthias ; Lee, James C; McGue, Matt ; Meitinger, Thomas ; Melzer, David ; Min, Josine L; Mohlke, Karen L; Vincent, John B; Nauck, Matthias ; Nickerson, Deborah ; Palotie, Aarno ; Pato, Michele ; Pirastu, Nicola ; McInnis, Melvin ; Richards, Brent J; Sala, Cinzia ; Salomaa, Veikko ; Schlessinger, David ; Schoenherr, Sebastian ; Slagboom, Eline P; Small, Kerrin ; Spector, Timothy ; Stambolian, Dwight ; Tuke, Marcus ; Tuomilehto, Jaakko ; Van den Berg, Leonard H; Van Rheenen, Wouter ; Volker, Uwe ; Wijmenga, Cisca ; Toniolo, Daniela ; Zeggini, Eleftheria ; Gasparini, Paolo ; Sampson, Matthew G; Wilson, James F; Frayling, Timothy ; de Bakker, Paul I W; Swertz, Morris A; McCarroll, Steven ; Kooperberg, Charles ; Dekker, Annelot ; Altshuler, David ; Willer, Cristen ; Iacono, William ; Ripatti, Samuli ; Soranzo, Nicole ; Walter, Klaudia ; Swaroop, Anand ; Cucca, Francesco ; Anderson, Carl A; Myers, Richard M; Boehnke, Michael ; McCarthy, Mark I; Durbin, Richard A reference panel of 64,976 haplotypes for genotype imputation. Journal Article Nat Genet, 48 (10), pp. 1279–1283, 2016, ISSN: 1546-1718 1061-4036. @article{mccarthy_reference_2016, title = {A reference panel of 64,976 haplotypes for genotype imputation.}, author = {McCarthy, Shane and Das, Sayantan and Kretzschmar, Warren and Delaneau, Olivier and Wood, Andrew R. and Teumer, Alexander and Kang, Hyun Min and Fuchsberger, Christian and Danecek, Petr and Sharp, Kevin and Luo, Yang and Sidore, Carlo and Kwong, Alan and Timpson, Nicholas and Koskinen, Seppo and Vrieze, Scott and Scott, Laura J. and Zhang, He and Mahajan, Anubha and Veldink, Jan and Peters, Ulrike and Pato, Carlos and van Duijn, Cornelia M. and Gillies, Christopher E. and Gandin, Ilaria and Mezzavilla, Massimo and Gilly, Arthur and Cocca, Massimiliano and Traglia, Michela and Angius, Andrea and Barrett, Jeffrey C. and Boomsma, Dorrett and Branham, Kari and Breen, Gerome and Brummett, Chad M. and Busonero, Fabio and Campbell, Harry and Chan, Andrew and Chen, Sai and Chew, Emily and Collins, Francis S. and Corbin, Laura J. and Smith, George Davey and Dedoussis, George and Dorr, Marcus and Farmaki, Aliki-Eleni and Ferrucci, Luigi and Forer, Lukas and Fraser, Ross M. and Gabriel, Stacey and Levy, Shawn and Groop, Leif and Harrison, Tabitha and Hattersley, Andrew and Holmen, Oddgeir L. and Hveem, Kristian and Kretzler, Matthias and Lee, James C. and McGue, Matt and Meitinger, Thomas and Melzer, David and Min, Josine L. and Mohlke, Karen L. and Vincent, John B. and Nauck, Matthias and Nickerson, Deborah and Palotie, Aarno and Pato, Michele and Pirastu, Nicola and McInnis, Melvin and Richards, J. Brent and Sala, Cinzia and Salomaa, Veikko and Schlessinger, David and Schoenherr, Sebastian and Slagboom, P. Eline and Small, Kerrin and Spector, Timothy and Stambolian, Dwight and Tuke, Marcus and Tuomilehto, Jaakko and Van den Berg, Leonard H. and Van Rheenen, Wouter and Volker, Uwe and Wijmenga, Cisca and Toniolo, Daniela and Zeggini, Eleftheria and Gasparini, Paolo and Sampson, Matthew G. and Wilson, James F. and Frayling, Timothy and de Bakker, Paul I. W. and Swertz, Morris A. and McCarroll, Steven and Kooperberg, Charles and Dekker, Annelot and Altshuler, David and Willer, Cristen and Iacono, William and Ripatti, Samuli and Soranzo, Nicole and Walter, Klaudia and Swaroop, Anand and Cucca, Francesco and Anderson, Carl A. and Myers, Richard M. and Boehnke, Michael and McCarthy, Mark I. and Durbin, Richard}, doi = {10.1038/ng.3643}, issn = {1546-1718 1061-4036}, year = {2016}, date = {2016-10-01}, journal = {Nat Genet}, volume = {48}, number = {10}, pages = {1279--1283}, abstract = {We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently. |
Delitala, Alessandro P; Steri, Maristella ; Pilia, Maria Grazia ; Dei, Mariano ; Lai, Sandra ; Delitala, Giuseppe ; Schlessinger, David ; Cucca, Francesco Menopause modulates the association between thyrotropin levels and lipid parameters: The SardiNIA study. Journal Article Maturitas, 92 , pp. 30–34, 2016, ISSN: 1873-4111 0378-5122. @article{delitala_menopause_2016, title = {Menopause modulates the association between thyrotropin levels and lipid parameters: The SardiNIA study.}, author = {Delitala, Alessandro P. and Steri, Maristella and Pilia, Maria Grazia and Dei, Mariano and Lai, Sandra and Delitala, Giuseppe and Schlessinger, David and Cucca, Francesco}, doi = {10.1016/j.maturitas.2016.07.003}, issn = {1873-4111 0378-5122}, year = {2016}, date = {2016-10-01}, journal = {Maturitas}, volume = {92}, pages = {30--34}, abstract = {OBJECTIVE: Thyroid hormone influences lipoprotein metabolism. The role of menopausal status in this association has not been extensively studied. The aim of the present study is to evaluate the association between lipid parameters and mild elevations of thyrotropin (TSH), and whether menopause influences this relationship. STUDY DESIGN: A cross-sectional study was conducted with a sample of 2,914 women (aged 14-102 years) from the SardiNIA study. MAIN OUTCOME MEASURES: The association of TSH with blood lipid levels was examined using regression analyses, according to menopausal status. RESULTS: Postmenopausal women had lower serum TSH concentrations and higher levels of total cholesterol, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), and triglycerides than did premenopausal women (p=0.001 or less for all). In premenopausal women, after adjusting for the confounders age, BMI, smoking, insulin and glycaemia, TSH showed a direct relation to the levels of total cholesterol (beta=0.046}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: Thyroid hormone influences lipoprotein metabolism. The role of menopausal status in this association has not been extensively studied. The aim of the present study is to evaluate the association between lipid parameters and mild elevations of thyrotropin (TSH), and whether menopause influences this relationship. STUDY DESIGN: A cross-sectional study was conducted with a sample of 2,914 women (aged 14-102 years) from the SardiNIA study. MAIN OUTCOME MEASURES: The association of TSH with blood lipid levels was examined using regression analyses, according to menopausal status. RESULTS: Postmenopausal women had lower serum TSH concentrations and higher levels of total cholesterol, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), and triglycerides than did premenopausal women (p=0.001 or less for all). In premenopausal women, after adjusting for the confounders age, BMI, smoking, insulin and glycaemia, TSH showed a direct relation to the levels of total cholesterol (beta=0.046 |
Das, Sayantan; Forer, Lukas; ö, Sebastian Sch; Sidore, Carlo; Locke, Adam E; Kwong, Alan; Vrieze, Scott I; Chew, Emily Y; Levy, Shawn; McGue, Matt; Schlessinger, David; Stambolian, Dwight; Loh, Po-Ru; Iacono, William G; Swaroop, Anand; Scott, Laura J; Cucca, Francesco; Kronenberg, Florian; Boehnke, Michael; ç, Gon; Fuchsberger, Christian Next-generation genotype imputation service and methods Journal Article Nature Genetics, 48 (10), pp. 1284–1287, 2016, ISSN: 1546-1718. @article{das_next-generation_2016, title = {Next-generation genotype imputation service and methods}, author = {Sayantan Das and Lukas Forer and Sebastian Sch{ö}nherr and Carlo Sidore and Adam E Locke and Alan Kwong and Scott I Vrieze and Emily Y Chew and Shawn Levy and Matt McGue and David Schlessinger and Dwight Stambolian and Po-Ru Loh and William G Iacono and Anand Swaroop and Laura J Scott and Francesco Cucca and Florian Kronenberg and Michael Boehnke and Gon{ç}alo R Abecasis and Christian Fuchsberger}, doi = {10.1038/ng.3656}, issn = {1546-1718}, year = {2016}, date = {2016-10-01}, journal = {Nature Genetics}, volume = {48}, number = {10}, pages = {1284--1287}, abstract = {Genotype imputation is a key component of genetic association studies, where it increases power, facilitates meta-analysis, and aids interpretation of signals. Genotype imputation is computationally demanding and, with current tools, typically requires access to a high-performance computing cluster and to a reference panel of sequenced genomes. Here we describe improvements to imputation machinery that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools. We also describe a new web-based service for imputation that facilitates access to new reference panels and greatly improves user experience and productivity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genotype imputation is a key component of genetic association studies, where it increases power, facilitates meta-analysis, and aids interpretation of signals. Genotype imputation is computationally demanding and, with current tools, typically requires access to a high-performance computing cluster and to a reference panel of sequenced genomes. Here we describe improvements to imputation machinery that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools. We also describe a new web-based service for imputation that facilitates access to new reference panels and greatly improves user experience and productivity. |
Scuteri, Angelo ; Morrell, Christopher H; Orru', Marco ; AlGhatrif, Majid ; Saba, Pier Sergio ; Terracciano, Antonio ; Ferreli, Liana Anna Pina ; Loi, Francesco ; Marongiu, Michele ; Pilia, Maria Grazia ; Delitala, Alessandro ; Tarasov, Kirill V; Schlessinger, David ; Ganau, Antonello ; Cucca, Francesco ; Lakatta, Edward G Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function in the SardiNIA study. Journal Article Int J Cardiol, 217 , pp. 92–98, 2016, ISSN: 1874-1754 0167-5273. @article{scuteri_gender_2016, title = {Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function in the SardiNIA study.}, author = {Scuteri, Angelo and Morrell, Christopher H. and Orru', Marco and AlGhatrif, Majid and Saba, Pier Sergio and Terracciano, Antonio and Ferreli, Liana Anna Pina and Loi, Francesco and Marongiu, Michele and Pilia, Maria Grazia and Delitala, Alessandro and Tarasov, Kirill V. and Schlessinger, David and Ganau, Antonello and Cucca, Francesco and Lakatta, Edward G.}, doi = {10.1016/j.ijcard.2016.04.172}, issn = {1874-1754 0167-5273}, year = {2016}, date = {2016-08-01}, journal = {Int J Cardiol}, volume = {217}, pages = {92--98}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Marongiu, Mara; Deiana, Manila; Marcia, Loredana; Sbardellati, Andrea; Asunis, Isadora; Meloni, Alessandra; Angius, Andrea; Cusano, Roberto; Loi, Angela; Crobu, Francesca; Fotia, Giorgio; Cucca, Francesco; Schlessinger, David; Crisponi, Laura Novel action of FOXL2 as mediator of Col1a2 gene autoregulation Journal Article Developmental Biology, 416 (1), pp. 200–211, 2016, ISSN: 1095-564X. @article{marongiu_novel_2016, title = {Novel action of FOXL2 as mediator of Col1a2 gene autoregulation}, author = {Mara Marongiu and Manila Deiana and Loredana Marcia and Andrea Sbardellati and Isadora Asunis and Alessandra Meloni and Andrea Angius and Roberto Cusano and Angela Loi and Francesca Crobu and Giorgio Fotia and Francesco Cucca and David Schlessinger and Laura Crisponi}, doi = {10.1016/j.ydbio.2016.05.022}, issn = {1095-564X}, year = {2016}, date = {2016-08-01}, journal = {Developmental Biology}, volume = {416}, number = {1}, pages = {200--211}, abstract = {FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2(-/-) mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2(-/-) mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause.}, keywords = {}, pubstate = {published}, tppubtype = {article} } FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2(-/-) mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2(-/-) mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause. |
Andlauer, Till F M; Buck, Dorothea ; Antony, Gisela ; Bayas, Antonios ; Bechmann, Lukas ; Berthele, Achim ; Chan, Andrew ; Gasperi, Christiane ; Gold, Ralf ; Graetz, Christiane ; Haas, Jurgen ; Hecker, Michael ; Infante-Duarte, Carmen ; Knop, Matthias ; Kumpfel, Tania ; Limmroth, Volker ; Linker, Ralf A; Loleit, Verena ; Luessi, Felix ; Meuth, Sven G; Muhlau, Mark ; Nischwitz, Sandra ; Paul, Friedemann ; Putz, Michael ; Ruck, Tobias ; Salmen, Anke ; Stangel, Martin ; Stellmann, Jan-Patrick ; Sturner, Klarissa H; Tackenberg, Bjorn ; Then Bergh, Florian ; Tumani, Hayrettin ; Warnke, Clemens ; Weber, Frank ; Wiendl, Heinz ; Wildemann, Brigitte ; Zettl, Uwe K; Ziemann, Ulf ; Zipp, Frauke ; Arloth, Janine ; Weber, Peter ; Radivojkov-Blagojevic, Milena ; Scheinhardt, Markus O; Dankowski, Theresa ; Bettecken, Thomas ; Lichtner, Peter ; Czamara, Darina ; Carrillo-Roa, Tania ; Binder, Elisabeth B; Berger, Klaus ; Bertram, Lars ; Franke, Andre ; Gieger, Christian ; Herms, Stefan ; Homuth, Georg ; Ising, Marcus ; Jockel, Karl-Heinz ; Kacprowski, Tim ; Kloiber, Stefan ; Laudes, Matthias ; Lieb, Wolfgang ; Lill, Christina M; Lucae, Susanne ; Meitinger, Thomas ; Moebus, Susanne ; Muller-Nurasyid, Martina ; Nothen, Markus M; Petersmann, Astrid ; Rawal, Rajesh ; Schminke, Ulf ; Strauch, Konstantin ; Volzke, Henry ; Waldenberger, Melanie ; Wellmann, Jurgen ; Porcu, Eleonora ; Mulas, Antonella ; Pitzalis, Maristella ; Sidore, Carlo ; Zara, Ilenia ; Cucca, Francesco ; Zoledziewska, Magdalena ; Ziegler, Andreas ; Hemmer, Bernhard ; Muller-Myhsok, Bertram Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Journal Article Sci Adv, 2 (6), pp. e1501678, 2016, ISSN: 2375-2548 2375-2548. @article{andlauer_novel_2016, title = {Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.}, author = {Andlauer, Till F. M. and Buck, Dorothea and Antony, Gisela and Bayas, Antonios and Bechmann, Lukas and Berthele, Achim and Chan, Andrew and Gasperi, Christiane and Gold, Ralf and Graetz, Christiane and Haas, Jurgen and Hecker, Michael and Infante-Duarte, Carmen and Knop, Matthias and Kumpfel, Tania and Limmroth, Volker and Linker, Ralf A. and Loleit, Verena and Luessi, Felix and Meuth, Sven G. and Muhlau, Mark and Nischwitz, Sandra and Paul, Friedemann and Putz, Michael and Ruck, Tobias and Salmen, Anke and Stangel, Martin and Stellmann, Jan-Patrick and Sturner, Klarissa H. and Tackenberg, Bjorn and Then Bergh, Florian and Tumani, Hayrettin and Warnke, Clemens and Weber, Frank and Wiendl, Heinz and Wildemann, Brigitte and Zettl, Uwe K. and Ziemann, Ulf and Zipp, Frauke and Arloth, Janine and Weber, Peter and Radivojkov-Blagojevic, Milena and Scheinhardt, Markus O. and Dankowski, Theresa and Bettecken, Thomas and Lichtner, Peter and Czamara, Darina and Carrillo-Roa, Tania and Binder, Elisabeth B. and Berger, Klaus and Bertram, Lars and Franke, Andre and Gieger, Christian and Herms, Stefan and Homuth, Georg and Ising, Marcus and Jockel, Karl-Heinz and Kacprowski, Tim and Kloiber, Stefan and Laudes, Matthias and Lieb, Wolfgang and Lill, Christina M. and Lucae, Susanne and Meitinger, Thomas and Moebus, Susanne and Muller-Nurasyid, Martina and Nothen, Markus M. and Petersmann, Astrid and Rawal, Rajesh and Schminke, Ulf and Strauch, Konstantin and Volzke, Henry and Waldenberger, Melanie and Wellmann, Jurgen and Porcu, Eleonora and Mulas, Antonella and Pitzalis, Maristella and Sidore, Carlo and Zara, Ilenia and Cucca, Francesco and Zoledziewska, Magdalena and Ziegler, Andreas and Hemmer, Bernhard and Muller-Myhsok, Bertram}, doi = {10.1126/sciadv.1501678}, issn = {2375-2548 2375-2548}, year = {2016}, date = {2016-06-01}, journal = {Sci Adv}, volume = {2}, number = {6}, pages = {e1501678}, abstract = {We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis. |
Demirkan, A; Lahti, J; Direk, N; Viktorin, A; Lunetta, K L; Terracciano, A; Nalls, M A; Tanaka, T; Hek, K; Fornage, M; Wellmann, J; Cornelis, M C; Ollila, H M; Yu, L; Smith, J A; Pilling, L C; Isaacs, A; Palotie, A; Zhuang, W V; Zonderman, A; Faul, J D; Sutin, A; Meirelles, O; Mulas, A; Hofman, A; Uitterlinden, A; Rivadeneira, F; Perola, M; Zhao, W; Salomaa, V; Yaffe, K; Luik, A I; Liu, Y; Ding, J; Lichtenstein, P; Landen, M; Widen, E; Weir, D R; Llewellyn, D J; Murray, A; Kardia, S L R; Eriksson, J G; Koenen, K; Magnusson, P K E; Ferrucci, L; Mosley, T H; Cucca, F; Oostra, B A; Bennett, D A; Paunio, T; Berger, K; Harris, T B; Pedersen, N L; Murabito, J M; Tiemeier, H; van Duijn, C M; Raikkonen, K Psychol Med, 46 (8), pp. 1613–1623, 2016, ISSN: 1469-8978 0033-2917. @article{demirkan_somatic_2016, title = {Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-Đ) scale: a meta-analysis of genome-wide association studies.}, author = {Demirkan, A. and Lahti, J. and Direk, N. and Viktorin, A. and Lunetta, K. L. and Terracciano, A. and Nalls, M. A. and Tanaka, T. and Hek, K. and Fornage, M. and Wellmann, J. and Cornelis, M. C. and Ollila, H. M. and Yu, L. and Smith, J. A. and Pilling, L. C. and Isaacs, A. and Palotie, A. and Zhuang, W. V. and Zonderman, A. and Faul, J. D. and Sutin, A. and Meirelles, O. and Mulas, A. and Hofman, A. and Uitterlinden, A. and Rivadeneira, F. and Perola, M. and Zhao, W. and Salomaa, V. and Yaffe, K. and Luik, A. I. and Liu, Y. and Ding, J. and Lichtenstein, P. and Landen, M. and Widen, E. and Weir, D. R. and Llewellyn, D. J. and Murray, A. and Kardia, S. L. R. and Eriksson, J. G. and Koenen, K. and Magnusson, P. K. E. and Ferrucci, L. and Mosley, T. H. and Cucca, F. and Oostra, B. A. and Bennett, D. A. and Paunio, T. and Berger, K. and Harris, T. B. and Pedersen, N. L. and Murabito, J. M. and Tiemeier, H. and van Duijn, C. M. and Raikkonen, K.}, doi = {10.1017/S0033291715002081}, issn = {1469-8978 0033-2917}, year = {2016}, date = {2016-06-01}, journal = {Psychol Med}, volume = {46}, number = {8}, pages = {1613--1623}, abstract = {BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 x 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 x 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 x 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 x 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings. |
Delitala, Alessandro P; Terracciano, Antonio; Fiorillo, Edoardo; ù, Valeria Orr; Schlessinger, David; Cucca, Francesco Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia Journal Article Journal of Affective Disorders, 191 , pp. 82–87, 2016, ISSN: 1573-2517. @article{delitala_depressive_2016, title = {Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia}, author = {Alessandro P Delitala and Antonio Terracciano and Edoardo Fiorillo and Valeria Orr{ù} and David Schlessinger and Francesco Cucca}, doi = {10.1016/j.jad.2015.11.019}, issn = {1573-2517}, year = {2016}, date = {2016-02-01}, journal = {Journal of Affective Disorders}, volume = {191}, pages = {82--87}, abstract = {OBJECTIVE: To evaluate the association between depressive symptoms and thyroid autoimmunity, and the effect of thyroid hormone on the risk of depression. METHODS: We included 3138 individuals from SardiNIA project, none of whom was taking thyroid medication and antidepressants. Thyrotropin (TSH), free thyroxine (FT4), and antibodies against thyroperoxidase (TPOAb) were measured in all the sample. Depressive symptoms were assessed with Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: We found no association between TPOAb and depressive symptoms and no linear association between TSH or FT4 levels and depressive symptoms. However, individuals in the lowest and highest FT4 quintiles showed a higher CES-D score compared to individuals in the middle quintile. In addition, participants in the lowest and highest FT4 quintiles had an increased risk of CES-D≥16 with odds ratios of 1.44 (95% CI=1.09-1.89) and 1.33 (95% CI=1.01-1.77), respectively. LIMITATIONS: Cross-sectional design of the study. CONCLUSIONS: A U-shaped relation was found between FT4 and depressive symptoms: compared to average FT4 values, both high and low thyroid function was associated with more depressive symptoms. Further studies are necessary to determine the exact cause-effect relation of this association.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To evaluate the association between depressive symptoms and thyroid autoimmunity, and the effect of thyroid hormone on the risk of depression. METHODS: We included 3138 individuals from SardiNIA project, none of whom was taking thyroid medication and antidepressants. Thyrotropin (TSH), free thyroxine (FT4), and antibodies against thyroperoxidase (TPOAb) were measured in all the sample. Depressive symptoms were assessed with Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: We found no association between TPOAb and depressive symptoms and no linear association between TSH or FT4 levels and depressive symptoms. However, individuals in the lowest and highest FT4 quintiles showed a higher CES-D score compared to individuals in the middle quintile. In addition, participants in the lowest and highest FT4 quintiles had an increased risk of CES-D≥16 with odds ratios of 1.44 (95% CI=1.09-1.89) and 1.33 (95% CI=1.01-1.77), respectively. LIMITATIONS: Cross-sectional design of the study. CONCLUSIONS: A U-shaped relation was found between FT4 and depressive symptoms: compared to average FT4 values, both high and low thyroid function was associated with more depressive symptoms. Further studies are necessary to determine the exact cause-effect relation of this association. |
Delitala, Alessandro P; Terracciano, Antonio ; Fiorillo, Edoardo ; Orru, Valeria ; Schlessinger, David ; Cucca, Francesco Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia. Journal Article J Affect Disord, 191 , pp. 82–87, 2016, ISSN: 1573-2517 0165-0327. @article{delitala_depressive_2016b, title = {Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia.}, author = {Delitala, Alessandro P. and Terracciano, Antonio and Fiorillo, Edoardo and Orru, Valeria and Schlessinger, David and Cucca, Francesco}, doi = {10.1016/j.jad.2015.11.019}, issn = {1573-2517 0165-0327}, year = {2016}, date = {2016-02-01}, journal = {J Affect Disord}, volume = {191}, pages = {82--87}, abstract = {OBJECTIVE: To evaluate the association between depressive symptoms and thyroid autoimmunity, and the effect of thyroid hormone on the risk of depression. METHODS: We included 3138 individuals from SardiNIA project, none of whom was taking thyroid medication and antidepressants. Thyrotropin (TSH), free thyroxine (FT4), and antibodies against thyroperoxidase (TPOAb) were measured in all the sample. Depressive symptoms were assessed with Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: We found no association between TPOAb and depressive symptoms and no linear association between TSH or FT4 levels and depressive symptoms. However, individuals in the lowest and highest FT4 quintiles showed a higher CES-D score compared to individuals in the middle quintile. In addition, participants in the lowest and highest FT4 quintiles had an increased risk of CES-Dtextgreater/=16 with odds ratios of 1.44 (95% CI=1.09-1.89) and 1.33 (95% CI=1.01-1.77), respectively. LIMITATIONS: Cross-sectional design of the study. CONCLUSIONS: A U-shaped relation was found between FT4 and depressive symptoms: compared to average FT4 values, both high and low thyroid function was associated with more depressive symptoms. Further studies are necessary to determine the exact cause-effect relation of this association.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To evaluate the association between depressive symptoms and thyroid autoimmunity, and the effect of thyroid hormone on the risk of depression. METHODS: We included 3138 individuals from SardiNIA project, none of whom was taking thyroid medication and antidepressants. Thyrotropin (TSH), free thyroxine (FT4), and antibodies against thyroperoxidase (TPOAb) were measured in all the sample. Depressive symptoms were assessed with Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: We found no association between TPOAb and depressive symptoms and no linear association between TSH or FT4 levels and depressive symptoms. However, individuals in the lowest and highest FT4 quintiles showed a higher CES-D score compared to individuals in the middle quintile. In addition, participants in the lowest and highest FT4 quintiles had an increased risk of CES-Dtextgreater/=16 with odds ratios of 1.44 (95% CI=1.09-1.89) and 1.33 (95% CI=1.01-1.77), respectively. LIMITATIONS: Cross-sectional design of the study. CONCLUSIONS: A U-shaped relation was found between FT4 and depressive symptoms: compared to average FT4 values, both high and low thyroid function was associated with more depressive symptoms. Further studies are necessary to determine the exact cause-effect relation of this association. |
de Vries, Paul S; Chasman, Daniel I; Sabater-Lleal, Maria; Chen, Ming-Huei; Huffman, Jennifer E; Steri, Maristella; Tang, Weihong; Teumer, Alexander; Marioni, Riccardo E; Grossmann, Vera; Hottenga, Jouke J; Trompet, Stella; ü, Martina M; Zhao, Jing Hua; Brody, Jennifer A; Kleber, Marcus E; Guo, Xiuqing; Wang, Jie Jin; Auer, Paul L; Attia, John R; Yanek, Lisa R; Ahluwalia, Tarunveer S; Lahti, Jari; Venturini, Cristina; Tanaka, Toshiko; Bielak, Lawrence F; Joshi, Peter K; Rocanin-Arjo, Ares; Kolcic, Ivana; Navarro, Pau; Rose, Lynda M; Oldmeadow, Christopher; Riess, Helene; Mazur, Johanna; Basu, Saonli; Goel, Anuj; Yang, Qiong; Ghanbari, Mohsen; Willemsen, Gonneke; Rumley, Ann; Fiorillo, Edoardo; de Craen, Anton J M; Grotevendt, Anne; Scott, Robert; Taylor, Kent D; Delgado, Graciela E; Yao, Jie; Kifley, Annette; Kooperberg, Charles; Qayyum, Rehan; Lopez, Lorna M; Berentzen, Tina L; ö, Katri R{ä}ikk; Mangino, Massimo; Bandinelli, Stefania; Peyser, Patricia A; Wild, Sarah; ë, David-Alexandre Tr{é}gou; Wright, Alan F; Marten, Jonathan; Zemunik, Tatijana; Morrison, Alanna C; Sennblad, Bengt; Tofler, Geoffrey; de Maat, Moniek P M; de Geus, Eco J C; Lowe, Gordon D; Zoledziewska, Magdalena; Sattar, Naveed; Binder, Harald; ö, Uwe V; Waldenberger, Melanie; Khaw, Kay-Tee; Mcknight, Barbara; Huang, Jie; Jenny, Nancy S; Holliday, Elizabeth G; Qi, Lihong; Mcevoy, Mark G; Becker, Diane M; Starr, John M; Sarin, Antti-Pekka; Hysi, Pirro G; Hernandez, Dena G; Jhun, Min A; Campbell, Harry; Hamsten, Anders; Rivadeneira, Fernando; Mcardle, Wendy L; Slagboom, Eline P; Zeller, Tanja; Koenig, Wolfgang; Psaty, Bruce M; Haritunians, Talin; Liu, Jingmin; Palotie, Aarno; é, Andr; Stott, David J; Hofman, Albert; Franco, Oscar H; Polasek, Ozren; Rudan, Igor; Morange, Pierre-Emmanuel; Wilson, James F; Kardia, Sharon L R; Ferrucci, Luigi; Spector, Tim D; Eriksson, Johan G; Hansen, Torben; Deary, Ian J; Becker, Lewis C; Scott, Rodney J; Mitchell, Paul; ä, Winfried M; Wareham, Nick J; Peters, Annette; Greinacher, Andreas; Wild, Philipp S; Jukema, Wouter J; Boomsma, Dorret I; Hayward, Caroline; Cucca, Francesco; Tracy, Russell; Watkins, Hugh; Reiner, Alex P; Folsom, Aaron R; Ridker, Paul M; O'Donnell, Christopher J; Smith, Nicholas L; Strachan, David P; Dehghan, Abbas A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration Journal Article Human Molecular Genetics, 25 (2), pp. 358–370, 2016, ISSN: 1460-2083. @article{de_vries_meta-analysis_2016, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration}, author = {Paul S de Vries and Daniel I Chasman and Maria Sabater-Lleal and Ming-Huei Chen and Jennifer E Huffman and Maristella Steri and Weihong Tang and Alexander Teumer and Riccardo E Marioni and Vera Grossmann and Jouke J Hottenga and Stella Trompet and Martina M{ü}ller-Nurasyid and Jing Hua Zhao and Jennifer A Brody and Marcus E Kleber and Xiuqing Guo and Jie Jin Wang and Paul L Auer and John R Attia and Lisa R Yanek and Tarunveer S Ahluwalia and Jari Lahti and Cristina Venturini and Toshiko Tanaka and Lawrence F Bielak and Peter K Joshi and Ares Rocanin-Arjo and Ivana Kolcic and Pau Navarro and Lynda M Rose and Christopher Oldmeadow and Helene Riess and Johanna Mazur and Saonli Basu and Anuj Goel and Qiong Yang and Mohsen Ghanbari and Gonneke Willemsen and Ann Rumley and Edoardo Fiorillo and Anton J M de Craen and Anne Grotevendt and Robert Scott and Kent D Taylor and Graciela E Delgado and Jie Yao and Annette Kifley and Charles Kooperberg and Rehan Qayyum and Lorna M Lopez and Tina L Berentzen and Katri R{ä}ikk{ö}nen and Massimo Mangino and Stefania Bandinelli and Patricia A Peyser and Sarah Wild and David-Alexandre Tr{é}gou{ë}t and Alan F Wright and Jonathan Marten and Tatijana Zemunik and Alanna C Morrison and Bengt Sennblad and Geoffrey Tofler and Moniek P M de Maat and Eco J C de Geus and Gordon D Lowe and Magdalena Zoledziewska and Naveed Sattar and Harald Binder and Uwe V{ö}lker and Melanie Waldenberger and Kay-Tee Khaw and Barbara Mcknight and Jie Huang and Nancy S Jenny and Elizabeth G Holliday and Lihong Qi and Mark G Mcevoy and Diane M Becker and John M Starr and Antti-Pekka Sarin and Pirro G Hysi and Dena G Hernandez and Min A Jhun and Harry Campbell and Anders Hamsten and Fernando Rivadeneira and Wendy L Mcardle and Eline P Slagboom and Tanja Zeller and Wolfgang Koenig and Bruce M Psaty and Talin Haritunians and Jingmin Liu and Aarno Palotie and Andr{é} G Uitterlinden and David J Stott and Albert Hofman and Oscar H Franco and Ozren Polasek and Igor Rudan and Pierre-Emmanuel Morange and James F Wilson and Sharon L R Kardia and Luigi Ferrucci and Tim D Spector and Johan G Eriksson and Torben Hansen and Ian J Deary and Lewis C Becker and Rodney J Scott and Paul Mitchell and Winfried M{ä}rz and Nick J Wareham and Annette Peters and Andreas Greinacher and Philipp S Wild and Wouter J Jukema and Dorret I Boomsma and Caroline Hayward and Francesco Cucca and Russell Tracy and Hugh Watkins and Alex P Reiner and Aaron R Folsom and Paul M Ridker and Christopher J O'Donnell and Nicholas L Smith and David P Strachan and Abbas Dehghan}, doi = {10.1093/hmg/ddv454}, issn = {1460-2083}, year = {2016}, date = {2016-01-01}, journal = {Human Molecular Genetics}, volume = {25}, number = {2}, pages = {358--370}, abstract = {Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration. |
2015 |
Delitala, A P; Filigheddu, F; Orru, M; AlGhatrif, M; Steri, M; Pilia, M G; Scuteri, A; Lobina, M; Piras, M G; Delitala, G; Lakatta, E G; Schlessinger, D; Cucca, F No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque. Journal Article Nutr Metab Cardiovasc Dis, 25 (12), pp. 1104–1110, 2015, ISSN: 1590-3729 0939-4753. @article{delitala_no_2015, title = {No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque.}, author = {Delitala, A. P. and Filigheddu, F. and Orru, M. and AlGhatrif, M. and Steri, M. and Pilia, M. G. and Scuteri, A. and Lobina, M. and Piras, M. G. and Delitala, G. and Lakatta, E. G. and Schlessinger, D. and Cucca, F.}, doi = {10.1016/j.numecd.2015.09.001}, issn = {1590-3729 0939-4753}, year = {2015}, date = {2015-12-01}, journal = {Nutr Metab Cardiovasc Dis}, volume = {25}, number = {12}, pages = {1104--1110}, abstract = {BACKGROUND AND AIMS: Increased carotid artery intima-media thickness (IMT) and the presence of plaques have been shown to be predictors of cardiovascular disease. The cardiovascular risk in patients with overt thyroid diseases is related to increased risk of atherosclerosis, but there has been no clear evidence about subclinical disorders. We have assessed whether subclinical thyroid dysfunction is associated with arterial thickening and plaque. METHODS AND RESULTS: The SardiNIA study is a population-based survey on the Italian island of Sardinia. We reviewed data from 5815 subjects (aged 14-102 years), none of whom had overt hyperthyroidism or hypothyroidism or was taking thyroid medication. Serum thyrotropin (TSH), free thyroxine, together with carotid ultrasound IMT and the presence of common carotid plaques were analysed in all subjects. Possible association of IMT and carotid plaques with thyroid parameters was evaluated by univariate and multivariate analyses. IMT was significantly associated with age, sex, smoking, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol, pulse pressure (PP), history of arterial hypertension, diabetes, and previous cardiovascular events (p = 0.001 or lower, R(2) = 0.47). Carotid plaques were predicted by age, sex, LDL, PP, history of diabetes, previous cardiovascular events, and the use of statins (p = 0.029 or lower). Thyroid hormone was not predictive of carotid atherosclerosis when adjusted for confounders. CONCLUSION: Thyroid hormone is not associated with increased IMT or with the presence of carotid artery plaque. Our data do not support the idea that treating subclinical disorders might help to prevent arterial remodelling or carotid atherosclerosis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND AND AIMS: Increased carotid artery intima-media thickness (IMT) and the presence of plaques have been shown to be predictors of cardiovascular disease. The cardiovascular risk in patients with overt thyroid diseases is related to increased risk of atherosclerosis, but there has been no clear evidence about subclinical disorders. We have assessed whether subclinical thyroid dysfunction is associated with arterial thickening and plaque. METHODS AND RESULTS: The SardiNIA study is a population-based survey on the Italian island of Sardinia. We reviewed data from 5815 subjects (aged 14-102 years), none of whom had overt hyperthyroidism or hypothyroidism or was taking thyroid medication. Serum thyrotropin (TSH), free thyroxine, together with carotid ultrasound IMT and the presence of common carotid plaques were analysed in all subjects. Possible association of IMT and carotid plaques with thyroid parameters was evaluated by univariate and multivariate analyses. IMT was significantly associated with age, sex, smoking, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol, pulse pressure (PP), history of arterial hypertension, diabetes, and previous cardiovascular events (p = 0.001 or lower, R(2) = 0.47). Carotid plaques were predicted by age, sex, LDL, PP, history of diabetes, previous cardiovascular events, and the use of statins (p = 0.029 or lower). Thyroid hormone was not predictive of carotid atherosclerosis when adjusted for confounders. CONCLUSION: Thyroid hormone is not associated with increased IMT or with the presence of carotid artery plaque. Our data do not support the idea that treating subclinical disorders might help to prevent arterial remodelling or carotid atherosclerosis. |
Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Porcu, Eleonora; Naitza, Silvia; Zoledziewska, Magdalena; Mulas, Antonella; Pistis, Giorgio; Steri, Maristella; Danjou, Fabrice; Kwong, Alan; Ortega Del Vecchyo, Vicente Diego ; Chiang, Charleston W K; Bragg-Gresham, Jennifer; Pitzalis, Maristella; Nagaraja, Ramaiah; Tarrier, Brendan; Brennan, Christine; Uzzau, Sergio; Fuchsberger, Christian; Atzeni, Rossano; Reinier, Frederic; Berutti, Riccardo; Huang, Jie; Timpson, Nicholas J; Toniolo, Daniela; Gasparini, Paolo; Malerba, Giovanni; Dedoussis, George; Zeggini, Eleftheria; Soranzo, Nicole; Jones, Chris; Lyons, Robert; Angius, Andrea; Kang, Hyun M; Novembre, John; Sanna, Serena; Schlessinger, David; Cucca, Francesco; ç, Gon Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers Journal Article Nature Genetics, 47 (11), pp. 1272–1281, 2015, ISSN: 1546-1718. @article{sidore_genome_2015, title = {Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers}, author = {Carlo Sidore and Fabio Busonero and Andrea Maschio and Eleonora Porcu and Silvia Naitza and Magdalena Zoledziewska and Antonella Mulas and Giorgio Pistis and Maristella Steri and Fabrice Danjou and Alan Kwong and Vicente Diego {Ortega Del Vecchyo} and Charleston W K Chiang and Jennifer Bragg-Gresham and Maristella Pitzalis and Ramaiah Nagaraja and Brendan Tarrier and Christine Brennan and Sergio Uzzau and Christian Fuchsberger and Rossano Atzeni and Frederic Reinier and Riccardo Berutti and Jie Huang and Nicholas J Timpson and Daniela Toniolo and Paolo Gasparini and Giovanni Malerba and George Dedoussis and Eleftheria Zeggini and Nicole Soranzo and Chris Jones and Robert Lyons and Andrea Angius and Hyun M Kang and John Novembre and Serena Sanna and David Schlessinger and Francesco Cucca and Gon{ç}alo R Abecasis}, doi = {10.1038/ng.3368}, issn = {1546-1718}, year = {2015}, date = {2015-11-01}, journal = {Nature Genetics}, volume = {47}, number = {11}, pages = {1272--1281}, abstract = {We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population. |
Danjou, Fabrice; Zoledziewska, Magdalena; Sidore, Carlo; Steri, Maristella; Busonero, Fabio; Maschio, Andrea; Mulas, Antonella; Perseu, Lucia; Barella, Susanna; Porcu, Eleonora; Pistis, Giorgio; Pitzalis, Maristella; Pala, Mauro; Menzel, Stephan; Metrustry, Sarah; Spector, Timothy D; Leoni, Lidia; Angius, Andrea; Uda, Manuela; Moi, Paolo; Thein, Swee Lay; Galanello, Renzo; ç, Gon; Schlessinger, David; Sanna, Serena; Cucca, Francesco Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels Journal Article Nature Genetics, 47 (11), pp. 1264–1271, 2015, ISSN: 1546-1718. @article{danjou_genome-wide_2015, title = {Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels}, author = {Fabrice Danjou and Magdalena Zoledziewska and Carlo Sidore and Maristella Steri and Fabio Busonero and Andrea Maschio and Antonella Mulas and Lucia Perseu and Susanna Barella and Eleonora Porcu and Giorgio Pistis and Maristella Pitzalis and Mauro Pala and Stephan Menzel and Sarah Metrustry and Timothy D Spector and Lidia Leoni and Andrea Angius and Manuela Uda and Paolo Moi and Swee Lay Thein and Renzo Galanello and Gon{ç}alo R Abecasis and David Schlessinger and Serena Sanna and Francesco Cucca}, doi = {10.1038/ng.3307}, issn = {1546-1718}, year = {2015}, date = {2015-11-01}, journal = {Nature Genetics}, volume = {47}, number = {11}, pages = {1264--1271}, abstract = {We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production. |
Zoledziewska, Magdalena; Sidore, Carlo; Chiang, Charleston W K; Sanna, Serena; Mulas, Antonella; Steri, Maristella; Busonero, Fabio; Marcus, Joseph H; Marongiu, Michele; Maschio, Andrea; Del Vecchyo, Diego Ortega ; Floris, Matteo; Meloni, Antonella; Delitala, Alessandro; Concas, Maria Pina; Murgia, Federico; Biino, Ginevra; Vaccargiu, Simona; Nagaraja, Ramaiah; Lohmueller, Kirk E; Consortium, UK10K; Timpson, Nicholas J; Soranzo, Nicole; Tachmazidou, Ioanna; Dedoussis, George; Zeggini, Eleftheria; Group, Understanding Society Scientific; Uzzau, Sergio; Jones, Chris; Lyons, Robert; Angius, Andrea; ç, Gon; Novembre, John; Schlessinger, David; Cucca, Francesco Height-reducing variants and selection for short stature in Sardinia Journal Article Nature Genetics, 47 (11), pp. 1352–1356, 2015, ISSN: 1546-1718. @article{zoledziewska_height-reducing_2015, title = {Height-reducing variants and selection for short stature in Sardinia}, author = {Magdalena Zoledziewska and Carlo Sidore and Charleston W K Chiang and Serena Sanna and Antonella Mulas and Maristella Steri and Fabio Busonero and Joseph H Marcus and Michele Marongiu and Andrea Maschio and Diego Ortega {Del Vecchyo} and Matteo Floris and Antonella Meloni and Alessandro Delitala and Maria Pina Concas and Federico Murgia and Ginevra Biino and Simona Vaccargiu and Ramaiah Nagaraja and Kirk E Lohmueller and UK10K Consortium and Nicholas J Timpson and Nicole Soranzo and Ioanna Tachmazidou and George Dedoussis and Eleftheria Zeggini and Understanding Society Scientific Group and Sergio Uzzau and Chris Jones and Robert Lyons and Andrea Angius and Gon{ç}alo R Abecasis and John Novembre and David Schlessinger and Francesco Cucca}, doi = {10.1038/ng.3403}, issn = {1546-1718}, year = {2015}, date = {2015-11-01}, journal = {Nature Genetics}, volume = {47}, number = {11}, pages = {1352--1356}, abstract = {We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals. |
Reinier, Frederic; Zoledziewska, Magdalena; Hanna, David; Smith, Josh D; Valentini, Maria; Zara, Ilenia; Berutti, Riccardo; Sanna, Serena; Oppo, Manuela; Cusano, Roberto; Satta, Rosanna; Montesu, Maria Antonietta; Jones, Chris; Cerimele, Decio; Nickerson, Deborah A; Angius, Andrea; Cucca, Francesco; Cottoni, Francesca; Crisponi, Laura Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies Journal Article Metabolism: Clinical and Experimental, 64 (11), pp. 1530–1540, 2015, ISSN: 1532-8600. @article{reinier_mandibular_2015, title = {Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies}, author = {Frederic Reinier and Magdalena Zoledziewska and David Hanna and Josh D Smith and Maria Valentini and Ilenia Zara and Riccardo Berutti and Serena Sanna and Manuela Oppo and Roberto Cusano and Rosanna Satta and Maria Antonietta Montesu and Chris Jones and Decio Cerimele and Deborah A Nickerson and Andrea Angius and Francesco Cucca and Francesca Cottoni and Laura Crisponi}, doi = {10.1016/j.metabol.2015.07.022}, issn = {1532-8600}, year = {2015}, date = {2015-11-01}, journal = {Metabolism: Clinical and Experimental}, volume = {64}, number = {11}, pages = {1530--1540}, abstract = {BACKGROUND: Lipodystrophies are a large heterogeneous group of genetic or acquired disorders characterized by generalized or partial fat loss, usually associated with metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Many efforts have been made in the last years in identifying the genetic etiologies of several lipodystrophy forms, although some remain to be elucidated. METHODS: We report here the clinical description of a woman with a rare severe lipodystrophic and progeroid syndrome associated with hypertriglyceridemia and diabetes whose genetic bases have been clarified through whole-exome sequencing (WES) analysis. RESULTS: This article reports the 5th MDPL (Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome) patient with the same de novo p.S605del mutation in POLD1. We provided further genetic evidence that this is a disease-causing mutation along with a plausible molecular mechanism responsible for this recurring event. Moreover we overviewed the current classification of the inherited forms of lipodystrophy, along with their underlying molecular basis. CONCLUSIONS: Progress in the identification of lipodystrophy genes will help in better understanding the role of the pathways involved in the complex physiology of fat. This will lead to new targets towards develop innovative therapeutic strategies for treating the disorder and its metabolic complications, as well as more common forms of adipose tissue redistribution as observed in the metabolic syndrome and type 2 diabetes.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Lipodystrophies are a large heterogeneous group of genetic or acquired disorders characterized by generalized or partial fat loss, usually associated with metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Many efforts have been made in the last years in identifying the genetic etiologies of several lipodystrophy forms, although some remain to be elucidated. METHODS: We report here the clinical description of a woman with a rare severe lipodystrophic and progeroid syndrome associated with hypertriglyceridemia and diabetes whose genetic bases have been clarified through whole-exome sequencing (WES) analysis. RESULTS: This article reports the 5th MDPL (Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome) patient with the same de novo p.S605del mutation in POLD1. We provided further genetic evidence that this is a disease-causing mutation along with a plausible molecular mechanism responsible for this recurring event. Moreover we overviewed the current classification of the inherited forms of lipodystrophy, along with their underlying molecular basis. CONCLUSIONS: Progress in the identification of lipodystrophy genes will help in better understanding the role of the pathways involved in the complex physiology of fat. This will lead to new targets towards develop innovative therapeutic strategies for treating the disorder and its metabolic complications, as well as more common forms of adipose tissue redistribution as observed in the metabolic syndrome and type 2 diabetes. |
Barizzone, Nadia ; Zara, Ilenia ; Sorosina, Melissa ; Lupoli, Sara ; Porcu, Eleonora ; Pitzalis, Maristella ; Zoledziewska, Magdalena ; Esposito, Federica ; Leone, Maurizio ; Mulas, Antonella ; Cocco, Eleonora ; Ferrigno, Paola ; Guerini, Franca R; Brambilla, Paola ; Farina, Gabriele ; Murru, Raffaele ; Deidda, Francesca ; Sanna, Sonia ; Loi, Alessia ; Barlassina, Cristina ; Vecchio, Domizia ; Zauli, Andrea ; Clarelli, Ferdinando ; Braga, Daniele ; Poddie, Fausto ; Cantello, Roberto ; Martinelli, Vittorio ; Comi, Giancarlo ; Frau, Jessica ; Lorefice, Lorena ; Pugliatti, Maura ; Rosati, Giulio ; Melis, Maurizio ; Marrosu, Maria G; Cusi, Daniele ; Cucca, Francesco ; Martinelli Boneschi, Filippo ; Sanna, Serena ; D'Alfonso, Sandra The burden of multiple sclerosis variants in continental Italians and Sardinians. Journal Article Mult Scler, 21 (11), pp. 1385–1395, 2015, ISSN: 1477-0970 1352-4585. @article{barizzone_burden_2015, title = {The burden of multiple sclerosis variants in continental Italians and Sardinians.}, author = {Barizzone, Nadia and Zara, Ilenia and Sorosina, Melissa and Lupoli, Sara and Porcu, Eleonora and Pitzalis, Maristella and Zoledziewska, Magdalena and Esposito, Federica and Leone, Maurizio and Mulas, Antonella and Cocco, Eleonora and Ferrigno, Paola and Guerini, Franca R. and Brambilla, Paola and Farina, Gabriele and Murru, Raffaele and Deidda, Francesca and Sanna, Sonia and Loi, Alessia and Barlassina, Cristina and Vecchio, Domizia and Zauli, Andrea and Clarelli, Ferdinando and Braga, Daniele and Poddie, Fausto and Cantello, Roberto and Martinelli, Vittorio and Comi, Giancarlo and Frau, Jessica and Lorefice, Lorena and Pugliatti, Maura and Rosati, Giulio and Melis, Maurizio and Marrosu, Maria G. and Cusi, Daniele and Cucca, Francesco and Martinelli Boneschi, Filippo and Sanna, Serena and D'Alfonso, Sandra}, doi = {10.1177/1352458515596599}, issn = {1477-0970 1352-4585}, year = {2015}, date = {2015-10-01}, journal = {Mult Scler}, volume = {21}, number = {11}, pages = {1385--1395}, abstract = {BACKGROUND: Recent studies identified textgreater 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. OBJECTIVE: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. METHODS: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. RESULTS: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. CONCLUSIONS: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Recent studies identified textgreater 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. OBJECTIVE: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. METHODS: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. RESULTS: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. CONCLUSIONS: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics. |
Lunetta, Kathryn L; Day, Felix R; Sulem, Patrick ; Ruth, Katherine S; Tung, Joyce Y; Hinds, David A; Esko, Tonu ; Elks, Cathy E; Altmaier, Elisabeth ; He, Chunyan ; Huffman, Jennifer E; Mihailov, Evelin ; Porcu, Eleonora ; Robino, Antonietta ; Rose, Lynda M; Schick, Ursula M; Stolk, Lisette ; Teumer, Alexander ; Thompson, Deborah J; Traglia, Michela ; Wang, Carol A; Yerges-Armstrong, Laura M; Antoniou, Antonis C; Barbieri, Caterina ; Coviello, Andrea D; Cucca, Francesco ; Demerath, Ellen W; Dunning, Alison M; Gandin, Ilaria ; Grove, Megan L; Gudbjartsson, Daniel F; Hocking, Lynne J; Hofman, Albert ; Huang, Jinyan ; Jackson, Rebecca D; Karasik, David ; Kriebel, Jennifer ; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia ; Li, Xin ; Luan, Jian'an ; Magi, Reedik ; Morrison, Alanna C; Padmanabhan, Sandosh ; Pirie, Ailith ; Polasek, Ozren ; Porteous, David ; Reiner, Alex P; Rivadeneira, Fernando ; Rudan, Igor ; Sala, Cinzia F; Schlessinger, David ; Scott, Robert A; Stockl, Doris ; Visser, Jenny A; Volker, Uwe ; Vozzi, Diego ; Wilson, James G; Zygmunt, Marek ; Boerwinkle, Eric ; Buring, Julie E; Crisponi, Laura ; Easton, Douglas F; Hayward, Caroline ; Hu, Frank B; Liu, Simin ; Metspalu, Andres ; Pennell, Craig E; Ridker, Paul M; Strauch, Konstantin ; Streeten, Elizabeth A; Toniolo, Daniela ; Uitterlinden, Andre G; Ulivi, Sheila ; Volzke, Henry ; Wareham, Nicholas J; Wellons, Melissa ; Franceschini, Nora ; Chasman, Daniel I; Thorsteinsdottir, Unnur ; Murray, Anna ; Stefansson, Kari ; Murabito, Joanne M; Ong, Ken K; Perry, John R B Rare coding variants and X-linked loci associated with age at menarche. Journal Article Nat Commun, 6 , pp. 7756, 2015, ISSN: 2041-1723 2041-1723. @article{lunetta_rare_2015, title = {Rare coding variants and X-linked loci associated with age at menarche.}, author = {Lunetta, Kathryn L. and Day, Felix R. and Sulem, Patrick and Ruth, Katherine S. and Tung, Joyce Y. and Hinds, David A. and Esko, Tonu and Elks, Cathy E. and Altmaier, Elisabeth and He, Chunyan and Huffman, Jennifer E. and Mihailov, Evelin and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M. and Schick, Ursula M. and Stolk, Lisette and Teumer, Alexander and Thompson, Deborah J. and Traglia, Michela and Wang, Carol A. and Yerges-Armstrong, Laura M. and Antoniou, Antonis C. and Barbieri, Caterina and Coviello, Andrea D. and Cucca, Francesco and Demerath, Ellen W. and Dunning, Alison M. and Gandin, Ilaria and Grove, Megan L. and Gudbjartsson, Daniel F. and Hocking, Lynne J. and Hofman, Albert and Huang, Jinyan and Jackson, Rebecca D. and Karasik, David and Kriebel, Jennifer and Lange, Ethan M. and Lange, Leslie A. and Langenberg, Claudia and Li, Xin and Luan, Jian'an and Magi, Reedik and Morrison, Alanna C. and Padmanabhan, Sandosh and Pirie, Ailith and Polasek, Ozren and Porteous, David and Reiner, Alex P. and Rivadeneira, Fernando and Rudan, Igor and Sala, Cinzia F. and Schlessinger, David and Scott, Robert A. and Stockl, Doris and Visser, Jenny A. and Volker, Uwe and Vozzi, Diego and Wilson, James G. and Zygmunt, Marek and Boerwinkle, Eric and Buring, Julie E. and Crisponi, Laura and Easton, Douglas F. and Hayward, Caroline and Hu, Frank B. and Liu, Simin and Metspalu, Andres and Pennell, Craig E. and Ridker, Paul M. and Strauch, Konstantin and Streeten, Elizabeth A. and Toniolo, Daniela and Uitterlinden, Andre G. and Ulivi, Sheila and Volzke, Henry and Wareham, Nicholas J. and Wellons, Melissa and Franceschini, Nora and Chasman, Daniel I. and Thorsteinsdottir, Unnur and Murray, Anna and Stefansson, Kari and Murabito, Joanne M. and Ong, Ken K. and Perry, John R. B.}, doi = {10.1038/ncomms8756}, issn = {2041-1723 2041-1723}, year = {2015}, date = {2015-08-01}, journal = {Nat Commun}, volume = {6}, pages = {7756}, abstract = {More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only approximately 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; Ptextless5 x 10(-8)). In addition, we identify common}, keywords = {}, pubstate = {published}, tppubtype = {article} } More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only approximately 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; Ptextless5 x 10(-8)). In addition, we identify common |
Ding, Jun ; Sidore, Carlo ; Butler, Thomas J; Wing, Mary Kate ; Qian, Yong ; Meirelles, Osorio ; Busonero, Fabio ; Tsoi, Lam C; Maschio, Andrea ; Angius, Andrea ; Kang, Hyun Min ; Nagaraja, Ramaiah ; Cucca, Francesco ; Abecasis, Goncalo R; Schlessinger, David Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of textasciitilde2,000 Sardinians Using Tailored Sequencing Analysis Tools. Journal Article PLoS Genet, 11 (7), pp. e1005306, 2015, ISSN: 1553-7404 1553-7390. @article{ding_assessing_2015, title = {Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of textasciitilde2,000 Sardinians Using Tailored Sequencing Analysis Tools.}, author = {Ding, Jun and Sidore, Carlo and Butler, Thomas J. and Wing, Mary Kate and Qian, Yong and Meirelles, Osorio and Busonero, Fabio and Tsoi, Lam C. and Maschio, Andrea and Angius, Andrea and Kang, Hyun Min and Nagaraja, Ramaiah and Cucca, Francesco and Abecasis, Goncalo R. and Schlessinger, David}, doi = {10.1371/journal.pgen.1005306}, issn = {1553-7404 1553-7390}, year = {2015}, date = {2015-07-01}, journal = {PLoS Genet}, volume = {11}, number = {7}, pages = {e1005306}, abstract = {DNA sequencing identifies common and rare genetic variants for association studies, but studies typically focus on variants in nuclear DNA and ignore the mitochondrial genome. In fact, analyzing variants in mitochondrial DNA (mtDNA) sequences presents special problems, which we resolve here with a general solution for the analysis of mtDNA in next-generation sequencing studies. The new program package comprises 1) an algorithm designed to identify mtDNA variants (i.e., homoplasmies and heteroplasmies), incorporating sequencing error rates at each base in a likelihood calculation and allowing allele fractions at a variant site to differ across individuals; and 2) an estimation of mtDNA copy number in a cell directly from whole-genome sequencing data. We also apply the methods to DNA sequence from lymphocytes of textasciitilde2,000 SardiNIA Project participants. As expected, mothers and offspring share all homoplasmies but a lesser proportion of heteroplasmies. Both homoplasmies and heteroplasmies show 5-fold higher transition/transversion ratios than variants in nuclear DNA. Also, heteroplasmy increases with age, though on average only textasciitilde1 heteroplasmy reaches the 4% level between ages 20 and 90. In addition, we find that mtDNA copy number averages textasciitilde110 copies/lymphocyte and is textasciitilde54% heritable, implying substantial genetic regulation of the level of mtDNA. Copy numbers also decrease modestly but significantly with age, and females on average have significantly more copies than males. The mtDNA copy numbers are significantly associated with waist circumference (p-value = 0.0031) and waist-hip ratio (p-value = 2.4x10-5), but not with body mass index, indicating an association with central fat distribution. To our knowledge, this is the largest population analysis to date of mtDNA dynamics, revealing the age-imposed increase in heteroplasmy, the relatively high heritability of copy number, and the association of copy number with metabolic traits.}, keywords = {}, pubstate = {published}, tppubtype = {article} } DNA sequencing identifies common and rare genetic variants for association studies, but studies typically focus on variants in nuclear DNA and ignore the mitochondrial genome. In fact, analyzing variants in mitochondrial DNA (mtDNA) sequences presents special problems, which we resolve here with a general solution for the analysis of mtDNA in next-generation sequencing studies. The new program package comprises 1) an algorithm designed to identify mtDNA variants (i.e., homoplasmies and heteroplasmies), incorporating sequencing error rates at each base in a likelihood calculation and allowing allele fractions at a variant site to differ across individuals; and 2) an estimation of mtDNA copy number in a cell directly from whole-genome sequencing data. We also apply the methods to DNA sequence from lymphocytes of textasciitilde2,000 SardiNIA Project participants. As expected, mothers and offspring share all homoplasmies but a lesser proportion of heteroplasmies. Both homoplasmies and heteroplasmies show 5-fold higher transition/transversion ratios than variants in nuclear DNA. Also, heteroplasmy increases with age, though on average only textasciitilde1 heteroplasmy reaches the 4% level between ages 20 and 90. In addition, we find that mtDNA copy number averages textasciitilde110 copies/lymphocyte and is textasciitilde54% heritable, implying substantial genetic regulation of the level of mtDNA. Copy numbers also decrease modestly but significantly with age, and females on average have significantly more copies than males. The mtDNA copy numbers are significantly associated with waist circumference (p-value = 0.0031) and waist-hip ratio (p-value = 2.4x10-5), but not with body mass index, indicating an association with central fat distribution. To our knowledge, this is the largest population analysis to date of mtDNA dynamics, revealing the age-imposed increase in heteroplasmy, the relatively high heritability of copy number, and the association of copy number with metabolic traits. |
Pistis, Giorgio ; Porcu, Eleonora ; Vrieze, Scott I; Sidore, Carlo ; Steri, Maristella ; Danjou, Fabrice ; Busonero, Fabio ; Mulas, Antonella ; Zoledziewska, Magdalena ; Maschio, Andrea ; Brennan, Christine ; Lai, Sandra ; Miller, Michael B; Marcelli, Marco ; Urru, Maria Francesca ; Pitzalis, Maristella ; Lyons, Robert H; Kang, Hyun M; Jones, Chris M; Angius, Andrea ; Iacono, William G; Schlessinger, David ; McGue, Matt ; Cucca, Francesco ; Abecasis, Goncalo R; Sanna, Serena Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs. Journal Article Eur J Hum Genet, 23 (7), pp. 975–983, 2015, ISSN: 1476-5438 1018-4813. @article{pistis_rare_2015, title = {Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs.}, author = {Pistis, Giorgio and Porcu, Eleonora and Vrieze, Scott I. and Sidore, Carlo and Steri, Maristella and Danjou, Fabrice and Busonero, Fabio and Mulas, Antonella and Zoledziewska, Magdalena and Maschio, Andrea and Brennan, Christine and Lai, Sandra and Miller, Michael B. and Marcelli, Marco and Urru, Maria Francesca and Pitzalis, Maristella and Lyons, Robert H. and Kang, Hyun M. and Jones, Chris M. and Angius, Andrea and Iacono, William G. and Schlessinger, David and McGue, Matt and Cucca, Francesco and Abecasis, Goncalo R. and Sanna, Serena}, doi = {10.1038/ejhg.2014.216}, issn = {1476-5438 1018-4813}, year = {2015}, date = {2015-07-01}, journal = {Eur J Hum Genet}, volume = {23}, number = {7}, pages = {975--983}, abstract = {The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost-effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study-specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating textasciitilde200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and}, keywords = {}, pubstate = {published}, tppubtype = {article} } The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost-effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study-specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating textasciitilde200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and |
Taylor, Peter N; Porcu, Eleonora ; Chew, Shelby ; Campbell, Purdey J; Traglia, Michela ; Brown, Suzanne J; Mullin, Benjamin H; Shihab, Hashem A; Min, Josine ; Walter, Klaudia ; Memari, Yasin ; Huang, Jie ; Barnes, Michael R; Beilby, John P; Charoen, Pimphen ; Danecek, Petr ; Dudbridge, Frank ; Forgetta, Vincenzo ; Greenwood, Celia ; Grundberg, Elin ; Johnson, Andrew D; Hui, Jennie ; Lim, Ee M; McCarthy, Shane ; Muddyman, Dawn ; Panicker, Vijay ; Perry, John R B; Bell, Jordana T; Yuan, Wei ; Relton, Caroline ; Gaunt, Tom ; Schlessinger, David ; Abecasis, Goncalo ; Cucca, Francesco ; Surdulescu, Gabriela L; Woltersdorf, Wolfram ; Zeggini, Eleftheria ; Zheng, Hou-Feng ; Toniolo, Daniela ; Dayan, Colin M; Naitza, Silvia ; Walsh, John P; Spector, Tim ; Smith, George Davey ; Durbin, Richard ; Richards, Brent J; Sanna, Serena ; Soranzo, Nicole ; Timpson, Nicholas J; Wilson, Scott G Erratum: Whole-genome sequence-based analysis of thyroid function. Journal Article Nat Commun, 6 , pp. 7172, 2015, ISSN: 2041-1723 2041-1723. @article{taylor_erratum:_2015, title = {Erratum: Whole-genome sequence-based analysis of thyroid function.}, author = {Taylor, Peter N. and Porcu, Eleonora and Chew, Shelby and Campbell, Purdey J. and Traglia, Michela and Brown, Suzanne J. and Mullin, Benjamin H. and Shihab, Hashem A. and Min, Josine and Walter, Klaudia and Memari, Yasin and Huang, Jie and Barnes, Michael R. and Beilby, John P. and Charoen, Pimphen and Danecek, Petr and Dudbridge, Frank and Forgetta, Vincenzo and Greenwood, Celia and Grundberg, Elin and Johnson, Andrew D. and Hui, Jennie and Lim, Ee M. and McCarthy, Shane and Muddyman, Dawn and Panicker, Vijay and Perry, John R. B. and Bell, Jordana T. and Yuan, Wei and Relton, Caroline and Gaunt, Tom and Schlessinger, David and Abecasis, Goncalo and Cucca, Francesco and Surdulescu, Gabriela L. and Woltersdorf, Wolfram and Zeggini, Eleftheria and Zheng, Hou-Feng and Toniolo, Daniela and Dayan, Colin M. and Naitza, Silvia and Walsh, John P. and Spector, Tim and Smith, George Davey and Durbin, Richard and Richards, J. Brent and Sanna, Serena and Soranzo, Nicole and Timpson, Nicholas J. and Wilson, Scott G.}, doi = {10.1038/ncomms8172}, issn = {2041-1723 2041-1723}, year = {2015}, date = {2015-05-01}, journal = {Nat Commun}, volume = {6}, pages = {7172}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Feng, Shuang ; Pistis, Giorgio ; Zhang, He ; Zawistowski, Matthew ; Mulas, Antonella ; Zoledziewska, Magdalena ; Holmen, Oddgeir L; Busonero, Fabio ; Sanna, Serena ; Hveem, Kristian ; Willer, Cristen ; Cucca, Francesco ; Liu, Dajiang J; Abecasis, Goncalo R Methods for association analysis and meta-analysis of rare variants in families. Journal Article Genet Epidemiol, 39 (4), pp. 227–238, 2015, ISSN: 1098-2272 0741-0395. @article{feng_methods_2015, title = {Methods for association analysis and meta-analysis of rare variants in families.}, author = {Feng, Shuang and Pistis, Giorgio and Zhang, He and Zawistowski, Matthew and Mulas, Antonella and Zoledziewska, Magdalena and Holmen, Oddgeir L. and Busonero, Fabio and Sanna, Serena and Hveem, Kristian and Willer, Cristen and Cucca, Francesco and Liu, Dajiang J. and Abecasis, Goncalo R.}, doi = {10.1002/gepi.21892}, issn = {1098-2272 0741-0395}, year = {2015}, date = {2015-05-01}, journal = {Genet Epidemiol}, volume = {39}, number = {4}, pages = {227--238}, abstract = {Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code. |
Francalacci, Paolo; Sanna, Daria; Useli, Antonella; Berutti, Riccardo; Barbato, Mario; Whalen, Michael B; Angius, Andrea; Sidore, Carlo; Alonso, Santos; Tofanelli, Sergio; Cucca, Francesco Detection of phylogenetically informative polymorphisms in the entire euchromatic portion of human Y chromosome from a Sardinian sample Journal Article BMC research notes, 8 , pp. 174, 2015, ISSN: 1756-0500. @article{francalacci_detection_2015, title = {Detection of phylogenetically informative polymorphisms in the entire euchromatic portion of human Y chromosome from a Sardinian sample}, author = {Paolo Francalacci and Daria Sanna and Antonella Useli and Riccardo Berutti and Mario Barbato and Michael B Whalen and Andrea Angius and Carlo Sidore and Santos Alonso and Sergio Tofanelli and Francesco Cucca}, doi = {10.1186/s13104-015-1130-z}, issn = {1756-0500}, year = {2015}, date = {2015-04-01}, journal = {BMC research notes}, volume = {8}, pages = {174}, abstract = {BACKGROUND: Next-Generation Sequencing methods have led to a great increase in phylogenetically useful markers within the male specific portion of the Y chromosome, but previous studies have limited themselves to the study of the X-degenerate regions. METHODS: DNA was extracted from peripheral blood samples of adult males whose paternal grandfathers were born in Sardinia. The DNA samples were sequenced, genotyped and subsequently analysed for variant calling for approximately 23.1 Mbp of the Y chromosome. A phylogenetic tree was built using Network 4.6 software. RESULTS: From low coverage whole genome sequencing of 1,194 Sardinian males, we extracted 20,155 phylogenetically informative single nucleotide polymorphisms from the whole euchromatic region, including the X-degenerate, X-transposed, and Ampliconic regions, along with variants in other unclassified chromosome intervals and in the readable sequences of the heterochromatic region. CONCLUSIONS: The non X-degenerate classes contain a significant portion of the phylogenetic variation of the whole chromosome and their inclusion in the analysis, almost doubling the number of informative polymorphisms, refining the known molecular phylogeny of the human Y chromosome.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Next-Generation Sequencing methods have led to a great increase in phylogenetically useful markers within the male specific portion of the Y chromosome, but previous studies have limited themselves to the study of the X-degenerate regions. METHODS: DNA was extracted from peripheral blood samples of adult males whose paternal grandfathers were born in Sardinia. The DNA samples were sequenced, genotyped and subsequently analysed for variant calling for approximately 23.1 Mbp of the Y chromosome. A phylogenetic tree was built using Network 4.6 software. RESULTS: From low coverage whole genome sequencing of 1,194 Sardinian males, we extracted 20,155 phylogenetically informative single nucleotide polymorphisms from the whole euchromatic region, including the X-degenerate, X-transposed, and Ampliconic regions, along with variants in other unclassified chromosome intervals and in the readable sequences of the heterochromatic region. CONCLUSIONS: The non X-degenerate classes contain a significant portion of the phylogenetic variation of the whole chromosome and their inclusion in the analysis, almost doubling the number of informative polymorphisms, refining the known molecular phylogeny of the human Y chromosome. |
Scuteri, Angelo ; Laurent, Stephane ; Cucca, Francesco ; Cockcroft, John ; Cunha, Pedro Guimaraes ; Manas, Leocadio Rodriguez ; Mattace Raso, Francesco U; Muiesan, Maria Lorenza ; Ryliskyte, Ligita ; Rietzschel, Ernst ; Strait, James ; Vlachopoulos, Charalambos ; Volzke, Henry ; Lakatta, Edward G; Nilsson, Peter M Metabolic syndrome across Europe: different clusters of risk factors. Journal Article Eur J Prev Cardiol, 22 (4), pp. 486–491, 2015, ISSN: 2047-4881 2047-4873. @article{scuteri_metabolic_2015, title = {Metabolic syndrome across Europe: different clusters of risk factors.}, author = {Scuteri, Angelo and Laurent, Stephane and Cucca, Francesco and Cockcroft, John and Cunha, Pedro Guimaraes and Manas, Leocadio Rodriguez and Mattace Raso, Francesco U. and Muiesan, Maria Lorenza and Ryliskyte, Ligita and Rietzschel, Ernst and Strait, James and Vlachopoulos, Charalambos and Volzke, Henry and Lakatta, Edward G. and Nilsson, Peter M.}, doi = {10.1177/2047487314525529}, issn = {2047-4881 2047-4873}, year = {2015}, date = {2015-04-01}, journal = {Eur J Prev Cardiol}, volume = {22}, number = {4}, pages = {486--491}, abstract = {BACKGROUND: Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. METHODS: In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose textgreater/=110 mg/dl; low HDL cholesterol, textless 40mg/dl for men or textless50 mg/dl for women; high triglycerides (T), textgreater/=150 mg/dl; elevated blood pressure (B), textgreater/=130/textgreater/=85 mmHg; abdominal obesity (W), waist circumference textgreater102 cm for men or textgreater88 cm for women. RESULTS: MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p textless 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p textless 0.0001) and in men and women (p textless 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively). CONCLUSIONS: The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. METHODS: In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose textgreater/=110 mg/dl; low HDL cholesterol, textless 40mg/dl for men or textless50 mg/dl for women; high triglycerides (T), textgreater/=150 mg/dl; elevated blood pressure (B), textgreater/=130/textgreater/=85 mmHg; abdominal obesity (W), waist circumference textgreater102 cm for men or textgreater88 cm for women. RESULTS: MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p textless 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p textless 0.0001) and in men and women (p textless 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively). CONCLUSIONS: The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries. |
Delitala, Alessandro P; Orru, Marco ; Filigheddu, Fabiana ; Pilia, Maria Grazia ; Delitala, Giuseppe ; Ganau, Antonello ; Saba, Pier Sergio ; Decandia, Federica ; Scuteri, Angelo ; Marongiu, Michele ; Lakatta, Edward G; Strait, James ; Cucca, Francesco Serum free thyroxine levels are positively associated with arterial stiffness in the SardiNIA study. Journal Article Clin Endocrinol (Oxf), 82 (4), pp. 592–597, 2015, ISSN: 1365-2265 0300-0664. @article{delitala_serum_2015, title = {Serum free thyroxine levels are positively associated with arterial stiffness in the SardiNIA study.}, author = {Delitala, Alessandro P. and Orru, Marco and Filigheddu, Fabiana and Pilia, Maria Grazia and Delitala, Giuseppe and Ganau, Antonello and Saba, Pier Sergio and Decandia, Federica and Scuteri, Angelo and Marongiu, Michele and Lakatta, Edward G. and Strait, James and Cucca, Francesco}, doi = {10.1111/cen.12532}, issn = {1365-2265 0300-0664}, year = {2015}, date = {2015-04-01}, journal = {Clin Endocrinol (Oxf)}, volume = {82}, number = {4}, pages = {592--597}, abstract = {OBJECTIVE: Thyroid dysfunction may accelerate atherosclerosis. Aortic pulse wave velocity (PWV) is an early index of arterial stiffness and an important risk factor for cardiovascular disease and might therefore be linked to changes in thyroid activity. We investigated the relationship between thyroid function and carotid-femoral PWV, as an index of arterial stiffness. DESIGN: Cross-sectional cohort study. PATIENTS: Participants from the SardiNIA study. Those being treated for thyroid diseases were excluded, yielding a sample of 5875 aged 14-102. MEASUREMENTS: Clinical parameters, blood tests including serum TSH and serum FT4, and carotid-femoral PWV were measured. RESULTS: After adjusting for confounders, a direct and linear association between FT4 and PWV was shown (multiple regression analysis). The model containing age, mean blood pressure, body mass index, heart rate, FT4, hypertension, diabetes and dyslipidaemia accounted for 55% of the variation in PWV. CONCLUSIONS: Like several other known risk factors, serum FT4 levels are associated with carotid-femoral PWV, suggesting that high FT4 levels have a detrimental effect on aortic stiffness and may contribute to ageing process of the vascular system. This finding may help to understand the pathogenesis of cardiovascular disease and contribute to improve prevention therapy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: Thyroid dysfunction may accelerate atherosclerosis. Aortic pulse wave velocity (PWV) is an early index of arterial stiffness and an important risk factor for cardiovascular disease and might therefore be linked to changes in thyroid activity. We investigated the relationship between thyroid function and carotid-femoral PWV, as an index of arterial stiffness. DESIGN: Cross-sectional cohort study. PATIENTS: Participants from the SardiNIA study. Those being treated for thyroid diseases were excluded, yielding a sample of 5875 aged 14-102. MEASUREMENTS: Clinical parameters, blood tests including serum TSH and serum FT4, and carotid-femoral PWV were measured. RESULTS: After adjusting for confounders, a direct and linear association between FT4 and PWV was shown (multiple regression analysis). The model containing age, mean blood pressure, body mass index, heart rate, FT4, hypertension, diabetes and dyslipidaemia accounted for 55% of the variation in PWV. CONCLUSIONS: Like several other known risk factors, serum FT4 levels are associated with carotid-femoral PWV, suggesting that high FT4 levels have a detrimental effect on aortic stiffness and may contribute to ageing process of the vascular system. This finding may help to understand the pathogenesis of cardiovascular disease and contribute to improve prevention therapy. |
Predazzi, Irene M; Sobota, Rafal S; Sanna, Serena ; Bush, William S; Bartlett, Jacquelaine ; Lilley, Jessica S; Linton, MacRae F; Schlessinger, David ; Cucca, Francesco ; Fazio, Sergio ; Williams, Scott M Sex-Specific Parental Effects on Offspring Lipid Levels. Journal Article J Am Heart Assoc, 4 (7), 2015, ISSN: 2047-9980 2047-9980. @article{predazzi_sex-specific_2015, title = {Sex-Specific Parental Effects on Offspring Lipid Levels.}, author = {Predazzi, Irene M. and Sobota, Rafal S. and Sanna, Serena and Bush, William S. and Bartlett, Jacquelaine and Lilley, Jessica S. and Linton, MacRae F. and Schlessinger, David and Cucca, Francesco and Fazio, Sergio and Williams, Scott M.}, doi = {10.1161/JAHA.115.001951}, issn = {2047-9980 2047-9980}, year = {2015}, date = {2015-01-01}, journal = {J Am Heart Assoc}, volume = {4}, number = {7}, abstract = {BACKGROUND: Plasma lipid levels are highly heritable traits, but known genetic loci can only explain a small portion of their heritability. METHODS AND RESULTS: In this study, we analyzed the role of parental levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) in explaining the values of the corresponding traits in adult offspring. We also evaluated the contribution of nongenetic factors that influence lipid traits (age, body mass index, smoking, medications, and menopause) alone and in combination with variability at the genetic loci known to associate with TC, LDL-C, HDL-C, and TG levels. We performed comparisons among different sex-specific regression models in 416 families from the Framingham Heart Study and 304 from the SardiNIA cohort. Models including parental lipid levels explain significantly more of the trait variation than models without these measures, explaining up to approximately 39% of the total trait variation. Of this variation, the parent-of-origin effect explains as much as approximately 15% and it does so in a sex-specific way. This observation is not owing to shared environment, given that spouse-pair correlations were negligible (textless1.5% explained variation in all cases) and is distinct from previous genetic and acquired factors that are known to influence serum lipid levels. CONCLUSIONS: These findings support the concept that unknown genetic and epigenetic contributors are responsible for most of the heritable component of the plasma lipid phenotype, and that, at present, the clinical utility of knowing age-matched parental lipid levels in assessing risk of dyslipidemia supersedes individual locus effects. Our results support the clinical utility of knowing parental lipid levels in assessing future risk of dyslipidemia.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Plasma lipid levels are highly heritable traits, but known genetic loci can only explain a small portion of their heritability. METHODS AND RESULTS: In this study, we analyzed the role of parental levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) in explaining the values of the corresponding traits in adult offspring. We also evaluated the contribution of nongenetic factors that influence lipid traits (age, body mass index, smoking, medications, and menopause) alone and in combination with variability at the genetic loci known to associate with TC, LDL-C, HDL-C, and TG levels. We performed comparisons among different sex-specific regression models in 416 families from the Framingham Heart Study and 304 from the SardiNIA cohort. Models including parental lipid levels explain significantly more of the trait variation than models without these measures, explaining up to approximately 39% of the total trait variation. Of this variation, the parent-of-origin effect explains as much as approximately 15% and it does so in a sex-specific way. This observation is not owing to shared environment, given that spouse-pair correlations were negligible (textless1.5% explained variation in all cases) and is distinct from previous genetic and acquired factors that are known to influence serum lipid levels. CONCLUSIONS: These findings support the concept that unknown genetic and epigenetic contributors are responsible for most of the heritable component of the plasma lipid phenotype, and that, at present, the clinical utility of knowing age-matched parental lipid levels in assessing risk of dyslipidemia supersedes individual locus effects. Our results support the clinical utility of knowing parental lipid levels in assessing future risk of dyslipidemia. |
Taylor, Peter N; Porcu, Eleonora ; Chew, Shelby ; Campbell, Purdey J; Traglia, Michela ; Brown, Suzanne J; Mullin, Benjamin H; Shihab, Hashem A; Min, Josine ; Walter, Klaudia ; Memari, Yasin ; Huang, Jie ; Barnes, Michael R; Beilby, John P; Charoen, Pimphen ; Danecek, Petr ; Dudbridge, Frank ; Forgetta, Vincenzo ; Greenwood, Celia ; Grundberg, Elin ; Johnson, Andrew D; Hui, Jennie ; Lim, Ee M; McCarthy, Shane ; Muddyman, Dawn ; Panicker, Vijay ; Perry, John R B; Bell, Jordana T; Yuan, Wei ; Relton, Caroline ; Gaunt, Tom ; Schlessinger, David ; Abecasis, Goncalo ; Cucca, Francesco ; Surdulescu, Gabriela L; Woltersdorf, Wolfram ; Zeggini, Eleftheria ; Zheng, Hou-Feng ; Toniolo, Daniela ; Dayan, Colin M; Naitza, Silvia ; Walsh, John P; Spector, Tim ; Davey Smith, George ; Durbin, Richard ; Richards, Brent J; Sanna, Serena ; Soranzo, Nicole ; Timpson, Nicholas J; Wilson, Scott G Whole-genome sequence-based analysis of thyroid function. Journal Article Nat Commun, 6 , pp. 5681, 2015, ISSN: 2041-1723 2041-1723. @article{taylor_whole-genome_2015, title = {Whole-genome sequence-based analysis of thyroid function.}, author = {Taylor, Peter N. and Porcu, Eleonora and Chew, Shelby and Campbell, Purdey J. and Traglia, Michela and Brown, Suzanne J. and Mullin, Benjamin H. and Shihab, Hashem A. and Min, Josine and Walter, Klaudia and Memari, Yasin and Huang, Jie and Barnes, Michael R. and Beilby, John P. and Charoen, Pimphen and Danecek, Petr and Dudbridge, Frank and Forgetta, Vincenzo and Greenwood, Celia and Grundberg, Elin and Johnson, Andrew D. and Hui, Jennie and Lim, Ee M. and McCarthy, Shane and Muddyman, Dawn and Panicker, Vijay and Perry, John R. B. and Bell, Jordana T. and Yuan, Wei and Relton, Caroline and Gaunt, Tom and Schlessinger, David and Abecasis, Goncalo and Cucca, Francesco and Surdulescu, Gabriela L. and Woltersdorf, Wolfram and Zeggini, Eleftheria and Zheng, Hou-Feng and Toniolo, Daniela and Dayan, Colin M. and Naitza, Silvia and Walsh, John P. and Spector, Tim and Davey Smith, George and Durbin, Richard and Richards, J. Brent and Sanna, Serena and Soranzo, Nicole and Timpson, Nicholas J. and Wilson, Scott G.}, doi = {10.1038/ncomms6681}, issn = {2041-1723 2041-1723}, year = {2015}, date = {2015-01-01}, journal = {Nat Commun}, volume = {6}, pages = {5681}, abstract = {Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAFtextgreater/=1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%}, keywords = {}, pubstate = {published}, tppubtype = {article} } Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAFtextgreater/=1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5% |
2014 |
Terracciano, Antonio ; Scuteri, Angelo ; Strait, James ; Sutin, Angelina R; Meirelles, Osorio ; Marongiu, Michele ; Orru, Marco ; Pilia, Maria Grazia ; Ferrucci, Luigi ; Cucca, Francesco ; Schlessinger, David ; Lakatta, Edward Are personality traits associated with white-coat and masked hypertension? Journal Article J Hypertens, 32 (10), pp. 1987–1992; discussion 1992, 2014, ISSN: 1473-5598 0263-6352. @article{terracciano_are_2014, title = {Are personality traits associated with white-coat and masked hypertension?}, author = {Terracciano, Antonio and Scuteri, Angelo and Strait, James and Sutin, Angelina R. and Meirelles, Osorio and Marongiu, Michele and Orru, Marco and Pilia, Maria Grazia and Ferrucci, Luigi and Cucca, Francesco and Schlessinger, David and Lakatta, Edward}, doi = {10.1097/HJH.0000000000000289}, issn = {1473-5598 0263-6352}, year = {2014}, date = {2014-10-01}, journal = {J Hypertens}, volume = {32}, number = {10}, pages = {1987--1992; discussion 1992}, abstract = {OBJECTIVES: Anxiety and other psychological dispositions are thought to be associated with blood pressure. This study tests whether personality traits have long-term associations with masked and white-coat effects. METHODS: A community-based sample of 2838 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory, and 7 years later, blood pressure was assessed in the clinic and with ambulatory monitoring. Logistic regressions were used to test whether anxiety, neuroticism, extraversion, openness, agreeableness, and conscientiousness predicted the white-coat and masked hypertension phenomena. Age, sex, and antihypertensive medication use were tested as moderators. RESULTS: Significant interactions were found between personality traits and antihypertensive medications in predicting masked and white-coat effects. Only among those taking antihypertensive medication, higher anxiety was associated with a higher risk of pseudo-resistant hypertension due to white-coat effect (odds ratio 1.39, 95% confidence interval 1.01-1.91) and higher conscientiousness was associated with a lower risk of masked uncontrolled hypertension (odds ratio 0.70, 95% confidence interval 0.49-0.99). There were no significant interactions with age or sex. CONCLUSIONS: Among those on antihypertensive medications, anxious individuals were more likely to have pseudo-resistant hypertension due to white-coat effect and less conscientious individuals were at increased risk of masked uncontrolled hypertension. Particularly among anxious and less conscientious individuals, ambulatory monitoring may improve the tailoring of pharmacological treatments.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVES: Anxiety and other psychological dispositions are thought to be associated with blood pressure. This study tests whether personality traits have long-term associations with masked and white-coat effects. METHODS: A community-based sample of 2838 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory, and 7 years later, blood pressure was assessed in the clinic and with ambulatory monitoring. Logistic regressions were used to test whether anxiety, neuroticism, extraversion, openness, agreeableness, and conscientiousness predicted the white-coat and masked hypertension phenomena. Age, sex, and antihypertensive medication use were tested as moderators. RESULTS: Significant interactions were found between personality traits and antihypertensive medications in predicting masked and white-coat effects. Only among those taking antihypertensive medication, higher anxiety was associated with a higher risk of pseudo-resistant hypertension due to white-coat effect (odds ratio 1.39, 95% confidence interval 1.01-1.91) and higher conscientiousness was associated with a lower risk of masked uncontrolled hypertension (odds ratio 0.70, 95% confidence interval 0.49-0.99). There were no significant interactions with age or sex. CONCLUSIONS: Among those on antihypertensive medications, anxious individuals were more likely to have pseudo-resistant hypertension due to white-coat effect and less conscientious individuals were at increased risk of masked uncontrolled hypertension. Particularly among anxious and less conscientious individuals, ambulatory monitoring may improve the tailoring of pharmacological treatments. |
Pani, Antonello ; Bragg-Gresham, Jennifer ; Masala, Marco ; Piras, Doloretta ; Atzeni, Alice ; Pilia, Maria G; Ferreli, Liana ; Balaci, Lenuta ; Curreli, Nicol{ò} ; Delitala, Alessandro ; Loi, Francesco ; Abecasis, Gon{ç}alo R; Schlessinger, David ; Cucca, Francesco Prevalence of CKD and its relationship to eGFR-related genetic loci and clinical risk factors in the SardiNIA study cohort. Journal Article Journal of the American Society of Nephrology : JASN, 25 (7), pp. 1533–44, 2014, ISSN: 1533-3450. @article{Pani2014, title = {Prevalence of CKD and its relationship to eGFR-related genetic loci and clinical risk factors in the SardiNIA study cohort.}, author = {Pani, Antonello and Bragg-Gresham, Jennifer and Masala, Marco and Piras, Doloretta and Atzeni, Alice and Pilia, Maria G and Ferreli, Liana and Balaci, Lenuta and Curreli, Nicol{ò} and Delitala, Alessandro and Loi, Francesco and Abecasis, Gon{ç}alo R and Schlessinger, David and Cucca, Francesco}, url = {http://www.jasn.org/cgi/doi/10.1681/ASN.2013060591 http://www.ncbi.nlm.nih.gov/pubmed/24511125 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4073426}, doi = {10.1681/ASN.2013060591}, issn = {1533-3450}, year = {2014}, date = {2014-07-01}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {25}, number = {7}, pages = {1533--44}, abstract = {The prevalence of CKD and of renal failure vary worldwide, yet parallel increases in leading risk factors explain only part of the differential prevalence. We measured CKD prevalence and eGFR, and their relationship with traditional and additional risk factors, in a Sardinian founder population cohort. The eGFR was calculated using equations from the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease studies. With use of the Kidney Disease Improving Global Outcomes guidelines, a cross-sectional analysis of 4842 individuals showed that CKD prevalence was 15.1%, including 3.6% of patients in the high-risk and 0.46% in the very-high-risk categories. Longitudinal analyses performed on 4074 of these individuals who completed three visits with an average follow-up of 7 years revealed that, consistent with other populations, average eGFR slope was -0.79 ml/min per 1.73 m(2) per year, but 11.4% of the participants had an eGFR decline >2.3 ml/min per 1.73 m(2) per year (fast decline). A genetic score was generated from 13 reported eGFR- and CKD-related loci, and univariable and multivariable analyses were applied to assess the relationship between clinical, ultrasonographic, and genetic variables with three outcomes: CKD, change in eGFR, and fast eGFR decline. Genetic risk score, older age, and female sex independently correlated with each outcome. Diabetes was associated with CKD prevalence, whereas hypertension and hyperuricemia correlated more strongly with fast eGFR decline. Diabetes, hypertension, hyperuricemia, and high baseline eGFR were associated with a decline of eGFR. Along with differential health practices, population variations in this spectrum of risk factors probably contributes to the variable CKD prevalence worldwide.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The prevalence of CKD and of renal failure vary worldwide, yet parallel increases in leading risk factors explain only part of the differential prevalence. We measured CKD prevalence and eGFR, and their relationship with traditional and additional risk factors, in a Sardinian founder population cohort. The eGFR was calculated using equations from the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease studies. With use of the Kidney Disease Improving Global Outcomes guidelines, a cross-sectional analysis of 4842 individuals showed that CKD prevalence was 15.1%, including 3.6% of patients in the high-risk and 0.46% in the very-high-risk categories. Longitudinal analyses performed on 4074 of these individuals who completed three visits with an average follow-up of 7 years revealed that, consistent with other populations, average eGFR slope was -0.79 ml/min per 1.73 m(2) per year, but 11.4% of the participants had an eGFR decline >2.3 ml/min per 1.73 m(2) per year (fast decline). A genetic score was generated from 13 reported eGFR- and CKD-related loci, and univariable and multivariable analyses were applied to assess the relationship between clinical, ultrasonographic, and genetic variables with three outcomes: CKD, change in eGFR, and fast eGFR decline. Genetic risk score, older age, and female sex independently correlated with each outcome. Diabetes was associated with CKD prevalence, whereas hypertension and hyperuricemia correlated more strongly with fast eGFR decline. Diabetes, hypertension, hyperuricemia, and high baseline eGFR were associated with a decline of eGFR. Along with differential health practices, population variations in this spectrum of risk factors probably contributes to the variable CKD prevalence worldwide. |
Delitala, Alessandro P; Pilia, Maria Grazia ; Ferreli, Liana ; Loi, Francesco ; Curreli, Nicolo ; Balaci, Lenuta ; Schlessinger, David ; Cucca, Francesco Prevalence of unknown thyroid disorders in a Sardinian cohort. Journal Article Eur J Endocrinol, 171 (1), pp. 143–149, 2014, ISSN: 1479-683X 0804-4643. @article{delitala_prevalence_2014, title = {Prevalence of unknown thyroid disorders in a Sardinian cohort.}, author = {Delitala, Alessandro P. and Pilia, Maria Grazia and Ferreli, Liana and Loi, Francesco and Curreli, Nicolo and Balaci, Lenuta and Schlessinger, David and Cucca, Francesco}, doi = {10.1530/EJE-14-0182}, issn = {1479-683X 0804-4643}, year = {2014}, date = {2014-07-01}, journal = {Eur J Endocrinol}, volume = {171}, number = {1}, pages = {143--149}, abstract = {OBJECTIVE: To assess thyroid function, the presence of thyroid antibodies, as well as the presence of goiter and/or nodules in subjects without a prior diagnosis of thyroid disorders, in a region with mild to moderate iodine deficiency. DESIGN AND METHODS: This cross-sectional study is based on data obtained from first and third visits of participants in the Sardinian survey. We performed two different analyses. In one, we assessed the prevalence of unknown thyroid dysfunctions among 6252 subjects who had a medical examination and blood collection for assays of thyrotropin, free thyroxine, and antibodies against thyroperoxidase (AbTPO) and against thyroglobulin (AbTG). In a second analysis, we evaluated the frequency of undiagnosed goiter and nodules among 3377 subjects who had a thyroid ultrasound scan. Subjects were excluded if they had a previous history of thyroid disorders or presence of goiter and/or nodules, or thyroid surgery, or if they were taking drugs that could impair thyroid function. RESULTS: We found a low prevalence of overt thyroid dysfunction (hyperthyroidism 0.4% and hypothyroidism 0.7%). The rates of subclinical hypothyroidism and hyperthyroidism were 4.7 and 2.4% respectively. Almost 16% of participants were positive for at least one antibody and 5.2% for both AbTG and AbTPO. Nodules were detected in 17.4% of subjects and the prevalence of goiter was 22.1%. CONCLUSIONS: Undiagnosed biochemical thyroid dysfunctions, unknown nodules, and goiter were common in subjects living in a mild to moderate iodine-deficient area. In this community, thyroid disorders often go undetected and screening could be reasonable in subjects at a higher risk.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To assess thyroid function, the presence of thyroid antibodies, as well as the presence of goiter and/or nodules in subjects without a prior diagnosis of thyroid disorders, in a region with mild to moderate iodine deficiency. DESIGN AND METHODS: This cross-sectional study is based on data obtained from first and third visits of participants in the Sardinian survey. We performed two different analyses. In one, we assessed the prevalence of unknown thyroid dysfunctions among 6252 subjects who had a medical examination and blood collection for assays of thyrotropin, free thyroxine, and antibodies against thyroperoxidase (AbTPO) and against thyroglobulin (AbTG). In a second analysis, we evaluated the frequency of undiagnosed goiter and nodules among 3377 subjects who had a thyroid ultrasound scan. Subjects were excluded if they had a previous history of thyroid disorders or presence of goiter and/or nodules, or thyroid surgery, or if they were taking drugs that could impair thyroid function. RESULTS: We found a low prevalence of overt thyroid dysfunction (hyperthyroidism 0.4% and hypothyroidism 0.7%). The rates of subclinical hypothyroidism and hyperthyroidism were 4.7 and 2.4% respectively. Almost 16% of participants were positive for at least one antibody and 5.2% for both AbTG and AbTPO. Nodules were detected in 17.4% of subjects and the prevalence of goiter was 22.1%. CONCLUSIONS: Undiagnosed biochemical thyroid dysfunctions, unknown nodules, and goiter were common in subjects living in a mild to moderate iodine-deficient area. In this community, thyroid disorders often go undetected and screening could be reasonable in subjects at a higher risk. |
Sikora, Martin ; Carpenter, Meredith L; Moreno-Estrada, Andres ; Henn, Brenna M; Underhill, Peter A; S{á}nchez-Quinto, Federico ; Zara, Ilenia ; Pitzalis, Maristella ; Sidore, Carlo ; Busonero, Fabio ; Maschio, Andrea ; Angius, Andrea ; Jones, Chris ; Mendoza-Revilla, Javier ; Nekhrizov, Georgi ; Dimitrova, Diana ; Theodossiev, Nikola ; Harkins, Timothy T; Keller, Andreas ; Maixner, Frank ; Zink, Albert ; Abecasis, Goncalo ; Sanna, Serena ; Cucca, Francesco ; Bustamante, Carlos D PLoS genetics, 10 (5), pp. e1004353, 2014, ISSN: 1553-7404. @article{Sikora2014, title = {Population genomic analysis of ancient and modern genomes yields new insights into the genetic ancestry of the Tyrolean Iceman and the genetic structure of Europe.}, author = {Sikora, Martin and Carpenter, Meredith L and Moreno-Estrada, Andres and Henn, Brenna M and Underhill, Peter A and S{á}nchez-Quinto, Federico and Zara, Ilenia and Pitzalis, Maristella and Sidore, Carlo and Busonero, Fabio and Maschio, Andrea and Angius, Andrea and Jones, Chris and Mendoza-Revilla, Javier and Nekhrizov, Georgi and Dimitrova, Diana and Theodossiev, Nikola and Harkins, Timothy T and Keller, Andreas and Maixner, Frank and Zink, Albert and Abecasis, Goncalo and Sanna, Serena and Cucca, Francesco and Bustamante, Carlos D}, editor = {Green, Richard E.}, url = {http://dx.plos.org/10.1371/journal.pgen.1004353 http://www.ncbi.nlm.nih.gov/pubmed/24809476 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4014435}, doi = {10.1371/journal.pgen.1004353}, issn = {1553-7404}, year = {2014}, date = {2014-05-01}, journal = {PLoS genetics}, volume = {10}, number = {5}, pages = {e1004353}, abstract = {Genome sequencing of the 5,300-year-old mummy of the Tyrolean Iceman, found in 1991 on a glacier near the border of Italy and Austria, has yielded new insights into his origin and relationship to modern European populations. A key finding of that study was an apparent recent common ancestry with individuals from Sardinia, based largely on the Y chromosome haplogroup and common autosomal SNP variation. Here, we compiled and analyzed genomic datasets from both modern and ancient Europeans, including genome sequence data from over 400 Sardinians and two ancient Thracians from Bulgaria, to investigate this result in greater detail and determine its implications for the genetic structure of Neolithic Europe. Using whole-genome sequencing data, we confirm that the Iceman is, indeed, most closely related to Sardinians. Furthermore, we show that this relationship extends to other individuals from cultural contexts associated with the spread of agriculture during the Neolithic transition, in contrast to individuals from a hunter-gatherer context. We hypothesize that this genetic affinity of ancient samples from different parts of Europe with Sardinians represents a common genetic component that was geographically widespread across Europe during the Neolithic, likely related to migrations and population expansions associated with the spread of agriculture.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genome sequencing of the 5,300-year-old mummy of the Tyrolean Iceman, found in 1991 on a glacier near the border of Italy and Austria, has yielded new insights into his origin and relationship to modern European populations. A key finding of that study was an apparent recent common ancestry with individuals from Sardinia, based largely on the Y chromosome haplogroup and common autosomal SNP variation. Here, we compiled and analyzed genomic datasets from both modern and ancient Europeans, including genome sequence data from over 400 Sardinians and two ancient Thracians from Bulgaria, to investigate this result in greater detail and determine its implications for the genetic structure of Neolithic Europe. Using whole-genome sequencing data, we confirm that the Iceman is, indeed, most closely related to Sardinians. Furthermore, we show that this relationship extends to other individuals from cultural contexts associated with the spread of agriculture during the Neolithic transition, in contrast to individuals from a hunter-gatherer context. We hypothesize that this genetic affinity of ancient samples from different parts of Europe with Sardinians represents a common genetic component that was geographically widespread across Europe during the Neolithic, likely related to migrations and population expansions associated with the spread of agriculture. |
Scuteri, Angelo ; Cunha, Pedro G; Rosei, Agabiti E; Badariere, Jolita ; Bekaert, Sofie ; Cockcroft, John R; Cotter, Jorge ; Cucca, Francesco ; De Buyzere, Marc L; De Meyer, Tim ; Ferrucci, Luigi ; Franco, Osca ; Gale, Nichols ; Gillebert, Thierry C; Hofman, A; Langlois, Michel ; Laucevicius, Aleksandras ; Laurent, Stephane ; Mattace Raso, Francesco U S; Morrell, Cristopher H; Muiesan, Maria Lorenza ; Munnery, Margaret M; Navickas, Rokas ; Oliveira, Pedro ; Orru', Marco ; Pilia, Maria Grazia ; Rietzschel, Ernst R; Ryliskyte, Ligita ; Salvetti, Massimo ; Schlessinger, David ; Sousa, Nuno ; Stefanadis, Christodoulos ; Strait, James ; Van daele, Caroline ; Villa, Isabel ; Vlachopoulos, Charalambos ; Witteman, Jacqueline ; Xaplanteris, Panagiotis ; Nilsson, Peter ; Lakatta, Edward G Arterial stiffness and influences of the metabolic syndrome: a cross-countries study. Journal Article Atherosclerosis, 233 (2), pp. 654–660, 2014, ISSN: 1879-1484 0021-9150. @article{scuteri_arterial_2014, title = {Arterial stiffness and influences of the metabolic syndrome: a cross-countries study.}, author = {Scuteri, Angelo and Cunha, Pedro G. and Rosei, E. Agabiti and Badariere, Jolita and Bekaert, Sofie and Cockcroft, John R. and Cotter, Jorge and Cucca, Francesco and De Buyzere, Marc L. and De Meyer, Tim and Ferrucci, Luigi and Franco, Osca and Gale, Nichols and Gillebert, Thierry C. and Hofman, A. and Langlois, Michel and Laucevicius, Aleksandras and Laurent, Stephane and Mattace Raso, Francesco U. S. and Morrell, Cristopher H. and Muiesan, Maria Lorenza and Munnery, Margaret M. and Navickas, Rokas and Oliveira, Pedro and Orru', Marco and Pilia, Maria Grazia and Rietzschel, Ernst R. and Ryliskyte, Ligita and Salvetti, Massimo and Schlessinger, David and Sousa, Nuno and Stefanadis, Christodoulos and Strait, James and Van daele, Caroline and Villa, Isabel and Vlachopoulos, Charalambos and Witteman, Jacqueline and Xaplanteris, Panagiotis and Nilsson, Peter and Lakatta, Edward G.}, doi = {10.1016/j.atherosclerosis.2014.01.041}, issn = {1879-1484 0021-9150}, year = {2014}, date = {2014-04-01}, journal = {Atherosclerosis}, volume = {233}, number = {2}, pages = {654--660}, abstract = {Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in textgreater/=3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components--even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus--in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in textgreater/=3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components--even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus--in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV). |
Elhaik, Eran ; Tatarinova, Tatiana ; Chebotarev, Dmitri ; Piras, Ignazio S; Maria Calo, Carla ; De Montis, Antonella ; Atzori, Manuela ; Marini, Monica ; Tofanelli, Sergio ; Francalacci, Paolo ; Pagani, Luca ; Tyler-Smith, Chris ; Xue, Yali ; Cucca, Francesco ; Schurr, Theodore G; Gaieski, Jill B; Melendez, Carlalynne ; Vilar, Miguel G; Owings, Amanda C; Gomez, Rocio ; Fujita, Ricardo ; Santos, Fabricio R; Comas, David ; Balanovsky, Oleg ; Balanovska, Elena ; Zalloua, Pierre ; Soodyall, Himla ; Pitchappan, Ramasamy ; Ganeshprasad, Arunkumar ; Hammer, Michael ; Matisoo-Smith, Lisa ; Wells, Spencer R Geographic population structure analysis of worldwide human populations infers their biogeographical origins. Journal Article Nat Commun, 5 , pp. 3513, 2014, ISSN: 2041-1723 2041-1723. @article{elhaik_geographic_2014, title = {Geographic population structure analysis of worldwide human populations infers their biogeographical origins.}, author = {Elhaik, Eran and Tatarinova, Tatiana and Chebotarev, Dmitri and Piras, Ignazio S. and Maria Calo, Carla and De Montis, Antonella and Atzori, Manuela and Marini, Monica and Tofanelli, Sergio and Francalacci, Paolo and Pagani, Luca and Tyler-Smith, Chris and Xue, Yali and Cucca, Francesco and Schurr, Theodore G. and Gaieski, Jill B. and Melendez, Carlalynne and Vilar, Miguel G. and Owings, Amanda C. and Gomez, Rocio and Fujita, Ricardo and Santos, Fabricio R. and Comas, David and Balanovsky, Oleg and Balanovska, Elena and Zalloua, Pierre and Soodyall, Himla and Pitchappan, Ramasamy and Ganeshprasad, Arunkumar and Hammer, Michael and Matisoo-Smith, Lisa and Wells, R. Spencer}, doi = {10.1038/ncomms4513}, issn = {2041-1723 2041-1723}, year = {2014}, date = {2014-04-01}, journal = {Nat Commun}, volume = {5}, pages = {3513}, abstract = {The search for a method that utilizes biological information to predict humans' place of origin has occupied scientists for millennia. Over the past four decades, scientists have employed genetic data in an effort to achieve this goal but with limited success. While biogeographical algorithms using next-generation sequencing data have achieved an accuracy of 700 km in Europe, they were inaccurate elsewhere. Here we describe the Geographic Population Structure (GPS) algorithm and demonstrate its accuracy with three data sets using 40,000-130,000 SNPs. GPS placed 83% of worldwide individuals in their country of origin. Applied to over 200 Sardinians villagers, GPS placed a quarter of them in their villages and most of the rest within 50 km of their villages. GPS's accuracy and power to infer the biogeography of worldwide individuals down to their country or, in some cases, village, of origin, underscores the promise of admixture-based methods for biogeography and has ramifications for genetic ancestry testing.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The search for a method that utilizes biological information to predict humans' place of origin has occupied scientists for millennia. Over the past four decades, scientists have employed genetic data in an effort to achieve this goal but with limited success. While biogeographical algorithms using next-generation sequencing data have achieved an accuracy of 700 km in Europe, they were inaccurate elsewhere. Here we describe the Geographic Population Structure (GPS) algorithm and demonstrate its accuracy with three data sets using 40,000-130,000 SNPs. GPS placed 83% of worldwide individuals in their country of origin. Applied to over 200 Sardinians villagers, GPS placed a quarter of them in their villages and most of the rest within 50 km of their villages. GPS's accuracy and power to infer the biogeography of worldwide individuals down to their country or, in some cases, village, of origin, underscores the promise of admixture-based methods for biogeography and has ramifications for genetic ancestry testing. |
Terracciano, Antonio ; Strait, James ; Scuteri, Angelo ; Meirelles, Osorio ; Sutin, Angelina R; Tarasov, Kirill ; Ding, Jun ; Marongiu, Michele ; Orru, Marco ; Pilia, Maria Grazia ; Cucca, Francesco ; Lakatta, Edward ; Schlessinger, David Personality traits and circadian blood pressure patterns: a 7-year prospective study. Journal Article Psychosom Med, 76 (3), pp. 237–243, 2014, ISSN: 1534-7796 0033-3174. @article{terracciano_personality_2014, title = {Personality traits and circadian blood pressure patterns: a 7-year prospective study.}, author = {Terracciano, Antonio and Strait, James and Scuteri, Angelo and Meirelles, Osorio and Sutin, Angelina R. and Tarasov, Kirill and Ding, Jun and Marongiu, Michele and Orru, Marco and Pilia, Maria Grazia and Cucca, Francesco and Lakatta, Edward and Schlessinger, David}, doi = {10.1097/PSY.0000000000000035}, issn = {1534-7796 0033-3174}, year = {2014}, date = {2014-04-01}, journal = {Psychosom Med}, volume = {76}, number = {3}, pages = {237--243}, abstract = {OBJECTIVE: A nighttime dip in blood pressure is associated with decreased risk of cardiovascular morbidity and mortality. We examined whether personality traits predict nighttime dipping blood pressure. METHODS: A community-based sample of 2848 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory and 7 years later were examined with 24-hour ambulatory blood pressure monitoring. The primary analyses examined the associations of personality traits with continuous and categorical measures of mean arterial, systolic, and diastolic blood pressure nighttime dipping. RESULTS: Agreeableness and conscientiousness were associated with more nocturnal blood pressure dipping (beta = .05 [p = .025] and beta = .07 [p textless .001], respectively) and lower systolic blood pressure at night (beta = -.05 [p = .018] and beta = -.03 [p = .072], respectively). Nondippers were particularly more impulsive (p = .009), less trusting (p = .004), and less self-disciplined (p = .001), but there was no significant association between nocturnal dipping blood pressure and trait anxiety (p = .78) or depression (p = .59). The associations were stronger when comparing extreme dippers (nighttime drop textgreater/= 20%) to reverse dippers (nighttime increase in blood pressure). Indeed, scoring 1 standard deviation higher on conscientiousness was associated with approximately 40% reduced risk of reverse dipping (odds ratio = 1.43, confidence interval = 1.08-1.91). CONCLUSIONS: We found evidence that reduced nighttime blood pressure dipping is associated with antagonism and impulsivity-related traits but not with measures of emotional vulnerability. The strongest associations were found with conscientiousness, a trait that may have a broad impact on cardiovascular health.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: A nighttime dip in blood pressure is associated with decreased risk of cardiovascular morbidity and mortality. We examined whether personality traits predict nighttime dipping blood pressure. METHODS: A community-based sample of 2848 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory and 7 years later were examined with 24-hour ambulatory blood pressure monitoring. The primary analyses examined the associations of personality traits with continuous and categorical measures of mean arterial, systolic, and diastolic blood pressure nighttime dipping. RESULTS: Agreeableness and conscientiousness were associated with more nocturnal blood pressure dipping (beta = .05 [p = .025] and beta = .07 [p textless .001], respectively) and lower systolic blood pressure at night (beta = -.05 [p = .018] and beta = -.03 [p = .072], respectively). Nondippers were particularly more impulsive (p = .009), less trusting (p = .004), and less self-disciplined (p = .001), but there was no significant association between nocturnal dipping blood pressure and trait anxiety (p = .78) or depression (p = .59). The associations were stronger when comparing extreme dippers (nighttime drop textgreater/= 20%) to reverse dippers (nighttime increase in blood pressure). Indeed, scoring 1 standard deviation higher on conscientiousness was associated with approximately 40% reduced risk of reverse dipping (odds ratio = 1.43, confidence interval = 1.08-1.91). CONCLUSIONS: We found evidence that reduced nighttime blood pressure dipping is associated with antagonism and impulsivity-related traits but not with measures of emotional vulnerability. The strongest associations were found with conscientiousness, a trait that may have a broad impact on cardiovascular health. |
Sutin, Angelina R; Cutler, Roy G; Camandola, Simonetta ; Uda, Manuela ; Feldman, Neil H; Cucca, Francesco ; Zonderman, Alan B; Mattson, Mark P; Ferrucci, Luigi ; Schlessinger, David ; Terracciano, Antonio Impulsivity is associated with uric acid: evidence from humans and mice. Journal Article Biol Psychiatry, 75 (1), pp. 31–37, 2014, ISSN: 1873-2402 0006-3223. @article{sutin_impulsivity_2014, title = {Impulsivity is associated with uric acid: evidence from humans and mice.}, author = {Sutin, Angelina R. and Cutler, Roy G. and Camandola, Simonetta and Uda, Manuela and Feldman, Neil H. and Cucca, Francesco and Zonderman, Alan B. and Mattson, Mark P. and Ferrucci, Luigi and Schlessinger, David and Terracciano, Antonio}, doi = {10.1016/j.biopsych.2013.02.024}, issn = {1873-2402 0006-3223}, year = {2014}, date = {2014-01-01}, journal = {Biol Psychiatry}, volume = {75}, number = {1}, pages = {31--37}, abstract = {BACKGROUND: The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. METHODS: Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. RESULTS: In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. CONCLUSIONS: Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. METHODS: Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. RESULTS: In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. CONCLUSIONS: Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention. |
Baumert, Jens; Huang, Jie; McKnight, Barbara; Sabater-Lleal, Maria; Steri, Maristella; Chu, Audrey Y; Trompet, Stella; Lopez, Lorna M; Fornage, Myriam; Teumer, Alexander; Tang, Weihong; Rudnicka, Alicja R; ä, Anders M; Hottenga, Jouke-Jan; Kavousi, Maryam; Lahti, Jari; Tanaka, Toshiko; Hayward, Caroline; Huffman, Jennifer E; Morange, Pierre-Emmanuel; Rose, Lynda M; Basu, Saonli; Rumley, Ann; Stott, David J; Buckley, Brendan M; de Craen, Anton J M; Sanna, Serena; Masala, Marco; Biffar, Reiner; Homuth, Georg; Silveira, Angela; Sennblad, Bengt; Goel, Anuj; Watkins, Hugh; ü, Martina M; ü, Regina R; Taylor, Kent; Chen, Ming-Huei; de Geus, Eco J C; Hofman, Albert; Witteman, Jacqueline C M; de Maat, Moniek P M; Palotie, Aarno; Davies, Gail; Siscovick, David S; Kolcic, Ivana; Wild, Sarah H; Song, Jaejoon; McArdle, Wendy L; Ford, Ian; Sattar, Naveed; Schlessinger, David; Grotevendt, Anne; Franzosi, Maria Grazia; Illig, Thomas; Waldenberger, Melanie; Lumley, Thomas; Tofler, Geoffrey H; Willemsen, Gonneke; é, Andr; Rivadeneira, Fernando; ö, Katri R{ä}ikk; Chasman, Daniel I; Folsom, Aaron R; Lowe, Gordon D; Westendorp, Rudi G J; Slagboom, Eline P; Cucca, Francesco; Wallaschofski, Henri; Strawbridge, Rona J; Seedorf, Udo; Koenig, Wolfgang; Bis, Joshua C; Mukamal, Kenneth J; van Dongen, Jenny; Widen, Elisabeth; Franco, Oscar H; Starr, John M; Liu, Kiang; Ferrucci, Luigi; Polasek, Ozren; Wilson, James F; Oudot-Mellakh, Tiphaine; Campbell, Harry; Navarro, Pau; Bandinelli, Stefania; Eriksson, Johan; Boomsma, Dorret I; Dehghan, Abbas; Clarke, Robert; Hamsten, Anders; Boerwinkle, Eric; Jukema, Wouter J; Naitza, Silvia; Ridker, Paul M; ö, Henry V; Deary, Ian J; Reiner, Alexander P; ë, David-Alexandre Tr{é}gou; O'Donnell, Christopher J; Strachan, David P; Peters, Annette; Smith, Nicholas L PloS One, 9 (12), pp. e111156, 2014, ISSN: 1932-6203. @article{baumert_no_2014, title = {No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects}, author = {Jens Baumert and Jie Huang and Barbara McKnight and Maria Sabater-Lleal and Maristella Steri and Audrey Y Chu and Stella Trompet and Lorna M Lopez and Myriam Fornage and Alexander Teumer and Weihong Tang and Alicja R Rudnicka and Anders M{ä}larstig and Jouke-Jan Hottenga and Maryam Kavousi and Jari Lahti and Toshiko Tanaka and Caroline Hayward and Jennifer E Huffman and Pierre-Emmanuel Morange and Lynda M Rose and Saonli Basu and Ann Rumley and David J Stott and Brendan M Buckley and Anton J M de Craen and Serena Sanna and Marco Masala and Reiner Biffar and Georg Homuth and Angela Silveira and Bengt Sennblad and Anuj Goel and Hugh Watkins and Martina M{ü}ller-Nurasyid and Regina R{ü}ckerl and Kent Taylor and Ming-Huei Chen and Eco J C de Geus and Albert Hofman and Jacqueline C M Witteman and Moniek P M de Maat and Aarno Palotie and Gail Davies and David S Siscovick and Ivana Kolcic and Sarah H Wild and Jaejoon Song and Wendy L McArdle and Ian Ford and Naveed Sattar and David Schlessinger and Anne Grotevendt and Maria Grazia Franzosi and Thomas Illig and Melanie Waldenberger and Thomas Lumley and Geoffrey H Tofler and Gonneke Willemsen and Andr{é} G Uitterlinden and Fernando Rivadeneira and Katri R{ä}ikk{ö}nen and Daniel I Chasman and Aaron R Folsom and Gordon D Lowe and Rudi G J Westendorp and Eline P Slagboom and Francesco Cucca and Henri Wallaschofski and Rona J Strawbridge and Udo Seedorf and Wolfgang Koenig and Joshua C Bis and Kenneth J Mukamal and Jenny van Dongen and Elisabeth Widen and Oscar H Franco and John M Starr and Kiang Liu and Luigi Ferrucci and Ozren Polasek and James F Wilson and Tiphaine Oudot-Mellakh and Harry Campbell and Pau Navarro and Stefania Bandinelli and Johan Eriksson and Dorret I Boomsma and Abbas Dehghan and Robert Clarke and Anders Hamsten and Eric Boerwinkle and Wouter J Jukema and Silvia Naitza and Paul M Ridker and Henry V{ö}lzke and Ian J Deary and Alexander P Reiner and David-Alexandre Tr{é}gou{ë}t and Christopher J O'Donnell and David P Strachan and Annette Peters and Nicholas L Smith}, doi = {10.1371/journal.pone.0111156}, issn = {1932-6203}, year = {2014}, date = {2014-01-01}, journal = {PloS One}, volume = {9}, number = {12}, pages = {e111156}, abstract = {Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations. |
2013 |
Stephens, Sarah H; Hartz, Sarah M; Hoft, Nicole R; Saccone, Nancy L; Corley, Robin C; Hewitt, John K; Hopfer, Christian J; Breslau, Naomi ; Coon, Hilary ; Chen, Xiangning ; Ducci, Francesca ; Dueker, Nicole ; Franceschini, Nora ; Frank, Josef ; Han, Younghun ; Hansel, Nadia N; Jiang, Chenhui ; Korhonen, Tellervo ; Lind, Penelope A; Liu, Jason ; Lyytikainen, Leo-Pekka ; Michel, Martha ; Shaffer, John R; Short, Susan E; Sun, Juzhong ; Teumer, Alexander ; Thompson, John R; Vogelzangs, Nicole ; Vink, Jacqueline M; Wenzlaff, Angela ; Wheeler, William ; Yang, Bao-Zhu ; Aggen, Steven H; Balmforth, Anthony J; Baumeister, Sebastian E; Beaty, Terri H; Benjamin, Daniel J; Bergen, Andrew W; Broms, Ulla ; Cesarini, David ; Chatterjee, Nilanjan ; Chen, Jingchun ; Cheng, Yu-Ching ; Cichon, Sven ; Couper, David ; Cucca, Francesco ; Dick, Danielle ; Foroud, Tatiana ; Furberg, Helena ; Giegling, Ina ; Gillespie, Nathan A; Gu, Fangyi ; Hall, Alistair S; Hallfors, Jenni ; Han, Shizhong ; Hartmann, Annette M; Heikkila, Kauko ; Hickie, Ian B; Hottenga, Jouke Jan ; Jousilahti, Pekka ; Kaakinen, Marika ; Kahonen, Mika ; Koellinger, Philipp D; Kittner, Stephen ; Konte, Bettina ; Landi, Maria-Teresa ; Laatikainen, Tiina ; Leppert, Mark ; Levy, Steven M; Mathias, Rasika A; McNeil, Daniel W; Medland, Sarah E; Montgomery, Grant W; Murray, Tanda ; Nauck, Matthias ; North, Kari E; Pare, Peter D; Pergadia, Michele ; Ruczinski, Ingo ; Salomaa, Veikko ; Viikari, Jorma ; Willemsen, Gonneke ; Barnes, Kathleen C; Boerwinkle, Eric ; Boomsma, Dorret I; Caporaso, Neil ; Edenberg, Howard J; Francks, Clyde ; Gelernter, Joel ; Grabe, Hans Jorgen ; Hops, Hyman ; Jarvelin, Marjo-Riitta ; Johannesson, Magnus ; Kendler, Kenneth S; Lehtimaki, Terho ; Magnusson, Patrik K E; Marazita, Mary L; Marchini, Jonathan ; Mitchell, Braxton D; Nothen, Markus M; Penninx, Brenda W; Raitakari, Olli ; Rietschel, Marcella ; Rujescu, Dan ; Samani, Nilesh J; Schwartz, Ann G; Shete, Sanjay ; Spitz, Margaret ; Swan, Gary E; Volzke, Henry ; Veijola, Juha ; Wei, Qingyi ; Amos, Chris ; Cannon, Dale S; Grucza, Richard ; Hatsukami, Dorothy ; Heath, Andrew ; Johnson, Eric O; Kaprio, Jaakko ; Madden, Pamela ; Martin, Nicholas G; Stevens, Victoria L; Weiss, Robert B; Kraft, Peter ; Bierut, Laura J; Ehringer, Marissa A Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Journal Article Genet Epidemiol, 37 (8), pp. 846–859, 2013, ISSN: 1098-2272 0741-0395. @article{stephens_distinct_2013, title = {Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.}, author = {Stephens, Sarah H. and Hartz, Sarah M. and Hoft, Nicole R. and Saccone, Nancy L. and Corley, Robin C. and Hewitt, John K. and Hopfer, Christian J. and Breslau, Naomi and Coon, Hilary and Chen, Xiangning and Ducci, Francesca and Dueker, Nicole and Franceschini, Nora and Frank, Josef and Han, Younghun and Hansel, Nadia N. and Jiang, Chenhui and Korhonen, Tellervo and Lind, Penelope A. and Liu, Jason and Lyytikainen, Leo-Pekka and Michel, Martha and Shaffer, John R. and Short, Susan E. and Sun, Juzhong and Teumer, Alexander and Thompson, John R. and Vogelzangs, Nicole and Vink, Jacqueline M. and Wenzlaff, Angela and Wheeler, William and Yang, Bao-Zhu and Aggen, Steven H. and Balmforth, Anthony J. and Baumeister, Sebastian E. and Beaty, Terri H. and Benjamin, Daniel J. and Bergen, Andrew W. and Broms, Ulla and Cesarini, David and Chatterjee, Nilanjan and Chen, Jingchun and Cheng, Yu-Ching and Cichon, Sven and Couper, David and Cucca, Francesco and Dick, Danielle and Foroud, Tatiana and Furberg, Helena and Giegling, Ina and Gillespie, Nathan A. and Gu, Fangyi and Hall, Alistair S. and Hallfors, Jenni and Han, Shizhong and Hartmann, Annette M. and Heikkila, Kauko and Hickie, Ian B. and Hottenga, Jouke Jan and Jousilahti, Pekka and Kaakinen, Marika and Kahonen, Mika and Koellinger, Philipp D. and Kittner, Stephen and Konte, Bettina and Landi, Maria-Teresa and Laatikainen, Tiina and Leppert, Mark and Levy, Steven M. and Mathias, Rasika A. and McNeil, Daniel W. and Medland, Sarah E. and Montgomery, Grant W. and Murray, Tanda and Nauck, Matthias and North, Kari E. and Pare, Peter D. and Pergadia, Michele and Ruczinski, Ingo and Salomaa, Veikko and Viikari, Jorma and Willemsen, Gonneke and Barnes, Kathleen C. and Boerwinkle, Eric and Boomsma, Dorret I. and Caporaso, Neil and Edenberg, Howard J. and Francks, Clyde and Gelernter, Joel and Grabe, Hans Jorgen and Hops, Hyman and Jarvelin, Marjo-Riitta and Johannesson, Magnus and Kendler, Kenneth S. and Lehtimaki, Terho and Magnusson, Patrik K. E. and Marazita, Mary L. and Marchini, Jonathan and Mitchell, Braxton D. and Nothen, Markus M. and Penninx, Brenda W. and Raitakari, Olli and Rietschel, Marcella and Rujescu, Dan and Samani, Nilesh J. and Schwartz, Ann G. and Shete, Sanjay and Spitz, Margaret and Swan, Gary E. and Volzke, Henry and Veijola, Juha and Wei, Qingyi and Amos, Chris and Cannon, Dale S. and Grucza, Richard and Hatsukami, Dorothy and Heath, Andrew and Johnson, Eric O. and Kaprio, Jaakko and Madden, Pamela and Martin, Nicholas G. and Stevens, Victoria L. and Weiss, Robert B. and Kraft, Peter and Bierut, Laura J. and Ehringer, Marissa A.}, doi = {10.1002/gepi.21760}, issn = {1098-2272 0741-0395}, year = {2013}, date = {2013-12-01}, journal = {Genet Epidemiol}, volume = {37}, number = {8}, pages = {846--859}, abstract = {Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02}, keywords = {}, pubstate = {published}, tppubtype = {article} } Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02 |
Muntoni, Sandro ; Mereu, Roberto ; Atzori, Luigi ; Mereu, Alessandra ; Galassi, Sabrina ; Corda, Stefania ; Frongia, Paola ; Angius, Efisio ; Pusceddu, Paolo ; Contu, Paolo ; Cucca, Francesco ; Congia, Mauro ; Muntoni, Sergio High meat consumption is associated with type 1 diabetes mellitus in a Sardinian case-control study. Journal Article Acta Diabetol, 50 (5), pp. 713–719, 2013, ISSN: 1432-5233 0940-5429. @article{muntoni_high_2013, title = {High meat consumption is associated with type 1 diabetes mellitus in a Sardinian case-control study.}, author = {Muntoni, Sandro and Mereu, Roberto and Atzori, Luigi and Mereu, Alessandra and Galassi, Sabrina and Corda, Stefania and Frongia, Paola and Angius, Efisio and Pusceddu, Paolo and Contu, Paolo and Cucca, Francesco and Congia, Mauro and Muntoni, Sergio}, doi = {10.1007/s00592-012-0385-2}, issn = {1432-5233 0940-5429}, year = {2013}, date = {2013-10-01}, journal = {Acta Diabetol}, volume = {50}, number = {5}, pages = {713--719}, abstract = {The large worldwide variation in type 1 diabetes incidence and increasing incidence over time points toward important environmental risk factors. Among them, nutrition plays an important role. The objective was to investigate the relationship between type 1 diabetes and nutritional factors in pregnancy and early in life. We carried out, using semi-quantitative food frequency questionnaires, a retrospective case-control study in 298 children of 0-15 years old, 145 of which were affected by type 1 diabetes. The diet of all children and of their mothers during pregnancy and lactation was assessed. In children, a statistically significant dose-response association between type 1 diabetes and the amount of meat consumption was found while no other nutritional factors were associated with the disease. High meat consumption seems to be an important early in life cofactor for type 1 diabetes development, although these findings need to be confirmed in wider prospective follow-up studies.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The large worldwide variation in type 1 diabetes incidence and increasing incidence over time points toward important environmental risk factors. Among them, nutrition plays an important role. The objective was to investigate the relationship between type 1 diabetes and nutritional factors in pregnancy and early in life. We carried out, using semi-quantitative food frequency questionnaires, a retrospective case-control study in 298 children of 0-15 years old, 145 of which were affected by type 1 diabetes. The diet of all children and of their mothers during pregnancy and lactation was assessed. In children, a statistically significant dose-response association between type 1 diabetes and the amount of meat consumption was found while no other nutritional factors were associated with the disease. High meat consumption seems to be an important early in life cofactor for type 1 diabetes development, although these findings need to be confirmed in wider prospective follow-up studies. |
Orrù, Valeria; Steri, Maristella; Sole, Gabriella; Sidore, Carlo; Virdis, Francesca; Dei, Mariano; Lai, Sandra; Zoledziewska, Magdalena; Busonero, Fabio; Mulas, Antonella; Floris, Matteo; Mentzen, Wieslawa I; Urru, Silvana A M; Olla, Stefania; Marongiu, Michele; Piras, Maria G; Lobina, Monia; Maschio, Andrea; Pitzalis, Maristella; Urru, Maria F; Marcelli, Marco; Cusano, Roberto; Deidda, Francesca; Serra, Valentina; Oppo, Manuela; Pilu, Rosella; Reinier, Frederic; Berutti, Riccardo; Pireddu, Luca; Zara, Ilenia; Porcu, Eleonora; Kwong, Alan; Brennan, Christine; Tarrier, Brendan; Lyons, Robert; Kang, Hyun M; Uzzau, Sergio; Atzeni, Rossano; Valentini, Maria; Firinu, Davide; Leoni, Lidia; Rotta, Gianluca; Naitza, Silvia; Angius, Andrea; Congia, Mauro; Whalen, Michael B; Jones, Chris M; Schlessinger, David; ç, Gon; Fiorillo, Edoardo; Sanna, Serena; Cucca, Francesco Genetic variants regulating immune cell levels in health and disease. Journal Article Cell, 155 (1), pp. 242–56, 2013, ISSN: 1097-4172. @article{orru_genetic_2013, title = {Genetic variants regulating immune cell levels in health and disease.}, author = {Valeria Orrù and Maristella Steri and Gabriella Sole and Carlo Sidore and Francesca Virdis and Mariano Dei and Sandra Lai and Magdalena Zoledziewska and Fabio Busonero and Antonella Mulas and Matteo Floris and Wieslawa I Mentzen and Silvana A M Urru and Stefania Olla and Michele Marongiu and Maria G Piras and Monia Lobina and Andrea Maschio and Maristella Pitzalis and Maria F Urru and Marco Marcelli and Roberto Cusano and Francesca Deidda and Valentina Serra and Manuela Oppo and Rosella Pilu and Frederic Reinier and Riccardo Berutti and Luca Pireddu and Ilenia Zara and Eleonora Porcu and Alan Kwong and Christine Brennan and Brendan Tarrier and Robert Lyons and Hyun M Kang and Sergio Uzzau and Rossano Atzeni and Maria Valentini and Davide Firinu and Lidia Leoni and Gianluca Rotta and Silvia Naitza and Andrea Angius and Mauro Congia and Michael B Whalen and Chris M Jones and David Schlessinger and Gon{ç}alo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco Cucca}, doi = {10.1016/j.cell.2013.08.041}, issn = {1097-4172}, year = {2013}, date = {2013-09-01}, journal = {Cell}, volume = {155}, number = {1}, pages = {242--56}, abstract = {The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease. |
Graff, Mariaelisa ; Ngwa, Julius S; Workalemahu, Tsegaselassie ; Homuth, Georg ; Schipf, Sabine ; Teumer, Alexander ; Volzke, Henry ; Wallaschofski, Henri ; Abecasis, Goncalo R; Edward, Lakatta ; Francesco, Cucca ; Sanna, Serena ; Scheet, Paul ; Schlessinger, David ; Sidore, Carlo ; Xiao, Xiangjun ; Wang, Zhaoming ; Chanock, Stephen J; Jacobs, Kevin B; Hayes, Richard B; Hu, Frank ; Van Dam, Rob M; Crout, Richard J; Marazita, Mary L; Shaffer, John R; Atwood, Larry D; Fox, Caroline S; Heard-Costa, Nancy L; White, Charles ; Choh, Audrey C; Czerwinski, Stefan A; Demerath, Ellen W; Dyer, Thomas D; Towne, Bradford ; Amin, Najaf ; Oostra, Ben A; Van Duijn, Cornelia M; Zillikens, Carola M; Esko, Tonu ; Nelis, Mari ; Nikopensius, Tit ; Metspalu, Andres ; Strachan, David P; Monda, Keri ; Qi, Lu ; North, Kari E; Cupples, Adrienne L; Gordon-Larsen, Penny ; Berndt, Sonja I Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. Journal Article Hum Mol Genet, 22 (17), pp. 3597–3607, 2013, ISSN: 1460-2083 0964-6906. @article{graff_genome-wide_2013, title = {Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course.}, author = {Graff, Mariaelisa and Ngwa, Julius S. and Workalemahu, Tsegaselassie and Homuth, Georg and Schipf, Sabine and Teumer, Alexander and Volzke, Henry and Wallaschofski, Henri and Abecasis, Goncalo R. and Edward, Lakatta and Francesco, Cucca and Sanna, Serena and Scheet, Paul and Schlessinger, David and Sidore, Carlo and Xiao, Xiangjun and Wang, Zhaoming and Chanock, Stephen J. and Jacobs, Kevin B. and Hayes, Richard B. and Hu, Frank and Van Dam, Rob M. and Crout, Richard J. and Marazita, Mary L. and Shaffer, John R. and Atwood, Larry D. and Fox, Caroline S. and Heard-Costa, Nancy L. and White, Charles and Choh, Audrey C. and Czerwinski, Stefan A. and Demerath, Ellen W. and Dyer, Thomas D. and Towne, Bradford and Amin, Najaf and Oostra, Ben A. and Van Duijn, Cornelia M. and Zillikens, M. Carola and Esko, Tonu and Nelis, Mari and Nikopensius, Tit and Metspalu, Andres and Strachan, David P. and Monda, Keri and Qi, Lu and North, Kari E. and Cupples, L. Adrienne and Gordon-Larsen, Penny and Berndt, Sonja I.}, doi = {10.1093/hmg/ddt205}, issn = {1460-2083 0964-6906}, year = {2013}, date = {2013-09-01}, journal = {Hum Mol Genet}, volume = {22}, number = {17}, pages = {3597--3607}, abstract = {Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P textless 5.0 x 10(-)(8)) near FTO (P = 3.72 x 10(-)(2)(3)), TMEM18 (P = 3.24 x 10(-)(1)(7)), MC4R (P = 4.41 x 10(-)(1)(7)), TNNI3K (P = 4.32 x 10(-)(1)(1)), SEC16B (P = 6.24 x 10(-)(9)), GNPDA2 (P = 1.11 x 10(-)(8)) and POMC (P = 4.94 x 10(-)(8)) as well as a potential secondary signal at the POMC locus (rs2118404}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P textless 5.0 x 10(-)(8)) near FTO (P = 3.72 x 10(-)(2)(3)), TMEM18 (P = 3.24 x 10(-)(1)(7)), MC4R (P = 4.41 x 10(-)(1)(7)), TNNI3K (P = 4.32 x 10(-)(1)(1)), SEC16B (P = 6.24 x 10(-)(9)), GNPDA2 (P = 1.11 x 10(-)(8)) and POMC (P = 4.94 x 10(-)(8)) as well as a potential secondary signal at the POMC locus (rs2118404 |
Francalacci, Paolo; Morelli, Laura; Angius, Andrea; Berutti, Riccardo; Reinier, Frederic; Atzeni, Rossano; Pilu, Rosella; Busonero, Fabio; Maschio, Andrea; Zara, Ilenia; Sanna, Daria; Useli, Antonella; Urru, Maria Francesca; Marcelli, Marco; Cusano, Roberto; Oppo, Manuela; Zoledziewska, Magdalena; Pitzalis, Maristella; Deidda, Francesca; Porcu, Eleonora; Poddie, Fausto; Kang, Hyun Min; Lyons, Robert; Tarrier, Brendan; Gresham, Jennifer Bragg; Li, Bingshan; Tofanelli, Sergio; Alonso, Santos; Dei, Mariano; Lai, Sandra; Mulas, Antonella; Whalen, Michael B; Uzzau, Sergio; Jones, Chris; Schlessinger, David; ç, Gon; Sanna, Serena; Sidore, Carlo; Cucca, Francesco Low-pass DNA sequencing of 1200 Sardinians reconstructs European Y-chromosome phylogeny Journal Article Science (New York, N.Y.), 341 (6145), pp. 565–569, 2013, ISSN: 1095-9203. @article{francalacci_low-pass_2013, title = {Low-pass DNA sequencing of 1200 Sardinians reconstructs European Y-chromosome phylogeny}, author = {Paolo Francalacci and Laura Morelli and Andrea Angius and Riccardo Berutti and Frederic Reinier and Rossano Atzeni and Rosella Pilu and Fabio Busonero and Andrea Maschio and Ilenia Zara and Daria Sanna and Antonella Useli and Maria Francesca Urru and Marco Marcelli and Roberto Cusano and Manuela Oppo and Magdalena Zoledziewska and Maristella Pitzalis and Francesca Deidda and Eleonora Porcu and Fausto Poddie and Hyun Min Kang and Robert Lyons and Brendan Tarrier and Jennifer Bragg Gresham and Bingshan Li and Sergio Tofanelli and Santos Alonso and Mariano Dei and Sandra Lai and Antonella Mulas and Michael B Whalen and Sergio Uzzau and Chris Jones and David Schlessinger and Gon{ç}alo R Abecasis and Serena Sanna and Carlo Sidore and Francesco Cucca}, doi = {10.1126/science.1237947}, issn = {1095-9203}, year = {2013}, date = {2013-08-01}, journal = {Science (New York, N.Y.)}, volume = {341}, number = {6145}, pages = {565--569}, abstract = {Genetic variation within the male-specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. Population sequencing of 1204 Sardinian males identified 11,763 MSY single-nucleotide polymorphisms, 6751 of which have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe, along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population textasciitilde7700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal the presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of textasciitilde180,000 to 200,000 years ago, which is consistent with previous mitochondrial DNA-based estimates.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genetic variation within the male-specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. Population sequencing of 1204 Sardinian males identified 11,763 MSY single-nucleotide polymorphisms, 6751 of which have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe, along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population textasciitilde7700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal the presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of textasciitilde180,000 to 200,000 years ago, which is consistent with previous mitochondrial DNA-based estimates. |
Sutin, Angelina R; Zonderman, Alan B; Uda, Manuela ; Deiana, Barbara ; Taub, Dennis D; Longo, Dan L; Ferrucci, Luigi ; Schlessinger, David ; Cucca, Francesco ; Terracciano, Antonio Personality traits and leptin. Journal Article Psychosom Med, 75 (5), pp. 505–509, 2013, ISSN: 1534-7796 0033-3174. @article{sutin_personality_2013, title = {Personality traits and leptin.}, author = {Sutin, Angelina R. and Zonderman, Alan B. and Uda, Manuela and Deiana, Barbara and Taub, Dennis D. and Longo, Dan L. and Ferrucci, Luigi and Schlessinger, David and Cucca, Francesco and Terracciano, Antonio}, doi = {10.1097/PSY.0b013e3182919ff4}, issn = {1534-7796 0033-3174}, year = {2013}, date = {2013-06-01}, journal = {Psychosom Med}, volume = {75}, number = {5}, pages = {505--509}, abstract = {OBJECTIVE: Personality traits related to high neuroticism and low conscientiousness are consistently associated with obesity. Hormones implicated in appetite and metabolism, such as leptin, may also be related to personality and may contribute to the association between these traits and obesity. The present research examined the association between leptin and Five Factor Model personality traits. METHODS: A total of 5214 participants (58% women; mean [standard deviation] age = 44.42 [15.93] years; range, 18-94 years) from the SardiNIA project completed the Revised NEO Personality Inventory, a comprehensive measure of personality traits, and their blood samples were assayed for leptin. RESULTS: As expected, lower conscientiousness was associated with higher circulating levels of leptin (r = -0.05, p textless .001), even after controlling for body mass index, waist circumference, or inflammatory markers (r = -0.05, p textless .001). Neuroticism, in contrast, was unrelated to leptin (r = 0.01}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: Personality traits related to high neuroticism and low conscientiousness are consistently associated with obesity. Hormones implicated in appetite and metabolism, such as leptin, may also be related to personality and may contribute to the association between these traits and obesity. The present research examined the association between leptin and Five Factor Model personality traits. METHODS: A total of 5214 participants (58% women; mean [standard deviation] age = 44.42 [15.93] years; range, 18-94 years) from the SardiNIA project completed the Revised NEO Personality Inventory, a comprehensive measure of personality traits, and their blood samples were assayed for leptin. RESULTS: As expected, lower conscientiousness was associated with higher circulating levels of leptin (r = -0.05, p textless .001), even after controlling for body mass index, waist circumference, or inflammatory markers (r = -0.05, p textless .001). Neuroticism, in contrast, was unrelated to leptin (r = 0.01 |
Meirelles, Osorio D; Ding, Jun ; Tanaka, Toshiko ; Sanna, Serena ; Yang, Hsih-Te ; Dudekula, Dawood B; Cucca, Francesco ; Ferrucci, Luigi ; Abecasis, Goncalo ; Schlessinger, David SHAVE: shrinkage estimator measured for multiple visits increases power in GWAS of quantitative traits. Journal Article Eur J Hum Genet, 21 (6), pp. 673–679, 2013, ISSN: 1476-5438 1018-4813. @article{meirelles_shave:_2013, title = {SHAVE: shrinkage estimator measured for multiple visits increases power in GWAS of quantitative traits.}, author = {Meirelles, Osorio D. and Ding, Jun and Tanaka, Toshiko and Sanna, Serena and Yang, Hsih-Te and Dudekula, Dawood B. and Cucca, Francesco and Ferrucci, Luigi and Abecasis, Goncalo and Schlessinger, David}, doi = {10.1038/ejhg.2012.215}, issn = {1476-5438 1018-4813}, year = {2013}, date = {2013-06-01}, journal = {Eur J Hum Genet}, volume = {21}, number = {6}, pages = {673--679}, abstract = {Measurement error and biological variability generate distortions in quantitative phenotypic data. In longitudinal studies with repeated measurements, the multiple measurements provide a route to reduce noise and correspondingly increase the strength of signals in genome-wide association studies (GWAS).To optimize noise correction, we have developed Shrunken Average (SHAVE), an approach using a Bayesian Shrinkage estimator. This estimator uses regression toward the mean for every individual as a function of (1) their average across visits; (2) their number of visits; and (3) the correlation between visits. Computer simulations support an increase in power, with results very similar to those expected by the assumptions of the model. The method was applied to a real data set for 14 anthropomorphic traits in approximately 6000 individuals enrolled in the SardiNIA project, with up to three visits (measurements) for each participant. Results show that additional measurements have a large impact on the strength of GWAS signals, especially when participants have different number of visits, with SHAVE showing a clear increase in power relative to single visits. In addition, we have derived a relation to assess the improvement in power as a function of number of visits and correlation between visits. It can also be applied in the optimization of experimental designs or usage of measuring devices. SHAVE is fast and easy to run, written in R and freely available online.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Measurement error and biological variability generate distortions in quantitative phenotypic data. In longitudinal studies with repeated measurements, the multiple measurements provide a route to reduce noise and correspondingly increase the strength of signals in genome-wide association studies (GWAS).To optimize noise correction, we have developed Shrunken Average (SHAVE), an approach using a Bayesian Shrinkage estimator. This estimator uses regression toward the mean for every individual as a function of (1) their average across visits; (2) their number of visits; and (3) the correlation between visits. Computer simulations support an increase in power, with results very similar to those expected by the assumptions of the model. The method was applied to a real data set for 14 anthropomorphic traits in approximately 6000 individuals enrolled in the SardiNIA project, with up to three visits (measurements) for each participant. Results show that additional measurements have a large impact on the strength of GWAS signals, especially when participants have different number of visits, with SHAVE showing a clear increase in power relative to single visits. In addition, we have derived a relation to assess the improvement in power as a function of number of visits and correlation between visits. It can also be applied in the optimization of experimental designs or usage of measuring devices. SHAVE is fast and easy to run, written in R and freely available online. |
Hek, Karin ; Demirkan, Ayse ; Lahti, Jari ; Terracciano, Antonio ; Teumer, Alexander ; Cornelis, Marilyn C; Amin, Najaf ; Bakshis, Erin ; Baumert, Jens ; Ding, Jingzhong ; Liu, Yongmei ; Marciante, Kristin ; Meirelles, Osorio ; Nalls, Michael A; Sun, Yan V; Vogelzangs, Nicole ; Yu, Lei ; Bandinelli, Stefania ; Benjamin, Emelia J; Bennett, David A; Boomsma, Dorret ; Cannas, Alessandra ; Coker, Laura H; de Geus, Eco ; De Jager, Philip L; Diez-Roux, Ana V; Purcell, Shaun ; Hu, Frank B; Rimma, Eric B; Hunter, David J; Jensen, Majken K; Curhan, Gary ; Rice, Kenneth ; Penman, Alan D; Rotter, Jerome I; Sotoodehnia, Nona ; Emeny, Rebecca ; Eriksson, Johan G; Evans, Denis A; Ferrucci, Luigi ; Fornage, Myriam ; Gudnason, Vilmundur ; Hofman, Albert ; Illig, Thomas ; Kardia, Sharon ; Kelly-Hayes, Margaret ; Koenen, Karestan ; Kraft, Peter ; Kuningas, Maris ; Massaro, Joseph M; Melzer, David ; Mulas, Antonella ; Mulder, Cornelis L; Murray, Anna ; Oostra, Ben A; Palotie, Aarno ; Penninx, Brenda ; Petersmann, Astrid ; Pilling, Luke C; Psaty, Bruce ; Rawal, Rajesh ; Reiman, Eric M; Schulz, Andrea ; Shulman, Joshua M; Singleton, Andrew B; Smith, Albert V; Sutin, Angelina R; Uitterlinden, Andre G; Volzke, Henry ; Widen, Elisabeth ; Yaffe, Kristine ; Zonderman, Alan B; Cucca, Francesco ; Harris, Tamara ; Ladwig, Karl-Heinz ; Llewellyn, David J; Raikkonen, Katri ; Tanaka, Toshiko ; van Duijn, Cornelia M; Grabe, Hans J; Launer, Lenore J; Lunetta, Kathryn L; Mosley, Thomas Jr H; Newman, Anne B; Tiemeier, Henning ; Murabito, Joanne A genome-wide association study of depressive symptoms. Journal Article Biol Psychiatry, 73 (7), pp. 667–678, 2013, ISSN: 1873-2402 0006-3223. @article{hek_genome-wide_2013, title = {A genome-wide association study of depressive symptoms.}, author = {Hek, Karin and Demirkan, Ayse and Lahti, Jari and Terracciano, Antonio and Teumer, Alexander and Cornelis, Marilyn C. and Amin, Najaf and Bakshis, Erin and Baumert, Jens and Ding, Jingzhong and Liu, Yongmei and Marciante, Kristin and Meirelles, Osorio and Nalls, Michael A. and Sun, Yan V. and Vogelzangs, Nicole and Yu, Lei and Bandinelli, Stefania and Benjamin, Emelia J. and Bennett, David A. and Boomsma, Dorret and Cannas, Alessandra and Coker, Laura H. and de Geus, Eco and De Jager, Philip L. and Diez-Roux, Ana V. and Purcell, Shaun and Hu, Frank B. and Rimma, Eric B. and Hunter, David J. and Jensen, Majken K. and Curhan, Gary and Rice, Kenneth and Penman, Alan D. and Rotter, Jerome I. and Sotoodehnia, Nona and Emeny, Rebecca and Eriksson, Johan G. and Evans, Denis A. and Ferrucci, Luigi and Fornage, Myriam and Gudnason, Vilmundur and Hofman, Albert and Illig, Thomas and Kardia, Sharon and Kelly-Hayes, Margaret and Koenen, Karestan and Kraft, Peter and Kuningas, Maris and Massaro, Joseph M. and Melzer, David and Mulas, Antonella and Mulder, Cornelis L. and Murray, Anna and Oostra, Ben A. and Palotie, Aarno and Penninx, Brenda and Petersmann, Astrid and Pilling, Luke C. and Psaty, Bruce and Rawal, Rajesh and Reiman, Eric M. and Schulz, Andrea and Shulman, Joshua M. and Singleton, Andrew B. and Smith, Albert V. and Sutin, Angelina R. and Uitterlinden, Andre G. and Volzke, Henry and Widen, Elisabeth and Yaffe, Kristine and Zonderman, Alan B. and Cucca, Francesco and Harris, Tamara and Ladwig, Karl-Heinz and Llewellyn, David J. and Raikkonen, Katri and Tanaka, Toshiko and van Duijn, Cornelia M. and Grabe, Hans J. and Launer, Lenore J. and Lunetta, Kathryn L. and Mosley, Thomas H. Jr and Newman, Anne B. and Tiemeier, Henning and Murabito, Joanne}, doi = {10.1016/j.biopsych.2012.09.033}, issn = {1873-2402 0006-3223}, year = {2013}, date = {2013-04-01}, journal = {Biol Psychiatry}, volume = {73}, number = {7}, pages = {667--678}, abstract = {BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (ptextless1x10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05x10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (ptextless1x10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05x10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21 |
Porcu, Eleonora ; Medici, Marco ; Pistis, Giorgio ; Volpato, Claudia B; Wilson, Scott G; Cappola, Anne R; Bos, Steffan D; Deelen, Joris ; den Heijer, Martin ; Freathy, Rachel M; Lahti, Jari ; Liu, Chunyu ; Lopez, Lorna M; Nolte, Ilja M; O'Connell, Jeffrey R; Tanaka, Toshiko ; Trompet, Stella ; Arnold, Alice ; Bandinelli, Stefania ; Beekman, Marian ; Bohringer, Stefan ; Brown, Suzanne J; Buckley, Brendan M; Camaschella, Clara ; de Craen, Anton J M; Davies, Gail ; de Visser, Marieke C H; Ford, Ian ; Forsen, Tom ; Frayling, Timothy M; Fugazzola, Laura ; Gogele, Martin ; Hattersley, Andrew T; Hermus, Ad R; Hofman, Albert ; Houwing-Duistermaat, Jeanine J; Jensen, Richard A; Kajantie, Eero ; Kloppenburg, Margreet ; Lim, Ee M; Masciullo, Corrado ; Mariotti, Stefano ; Minelli, Cosetta ; Mitchell, Braxton D; Nagaraja, Ramaiah ; Netea-Maier, Romana T; Palotie, Aarno ; Persani, Luca ; Piras, Maria G; Psaty, Bruce M; Raikkonen, Katri ; Richards, Brent J; Rivadeneira, Fernando ; Sala, Cinzia ; Sabra, Mona M; Sattar, Naveed ; Shields, Beverley M; Soranzo, Nicole ; Starr, John M; Stott, David J; Sweep, Fred C G J; Usala, Gianluca ; van der Klauw, Melanie M; van Heemst, Diana ; van Mullem, Alies ; Vermeulen, Sita H; Visser, Edward W; Walsh, John P; Westendorp, Rudi G J; Widen, Elisabeth ; Zhai, Guangju ; Cucca, Francesco ; Deary, Ian J; Eriksson, Johan G; Ferrucci, Luigi ; Fox, Caroline S; Jukema, Wouter J; Kiemeney, Lambertus A; Pramstaller, Peter P; Schlessinger, David ; Shuldiner, Alan R; Slagboom, Eline P; Uitterlinden, Andre G; Vaidya, Bijay ; Visser, Theo J; Wolffenbuttel, Bruce H R; Meulenbelt, Ingrid ; Rotter, Jerome I; Spector, Tim D; Hicks, Andrew A; Toniolo, Daniela ; Sanna, Serena ; Peeters, Robin P; Naitza, Silvia A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. Journal Article PLoS Genet, 9 (2), pp. e1003266, 2013, ISSN: 1553-7404 1553-7390. @article{porcu_meta-analysis_2013, title = {A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.}, author = {Porcu, Eleonora and Medici, Marco and Pistis, Giorgio and Volpato, Claudia B. and Wilson, Scott G. and Cappola, Anne R. and Bos, Steffan D. and Deelen, Joris and den Heijer, Martin and Freathy, Rachel M. and Lahti, Jari and Liu, Chunyu and Lopez, Lorna M. and Nolte, Ilja M. and O'Connell, Jeffrey R. and Tanaka, Toshiko and Trompet, Stella and Arnold, Alice and Bandinelli, Stefania and Beekman, Marian and Bohringer, Stefan and Brown, Suzanne J. and Buckley, Brendan M. and Camaschella, Clara and de Craen, Anton J. M. and Davies, Gail and de Visser, Marieke C. H. and Ford, Ian and Forsen, Tom and Frayling, Timothy M. and Fugazzola, Laura and Gogele, Martin and Hattersley, Andrew T. and Hermus, Ad R. and Hofman, Albert and Houwing-Duistermaat, Jeanine J. and Jensen, Richard A. and Kajantie, Eero and Kloppenburg, Margreet and Lim, Ee M. and Masciullo, Corrado and Mariotti, Stefano and Minelli, Cosetta and Mitchell, Braxton D. and Nagaraja, Ramaiah and Netea-Maier, Romana T. and Palotie, Aarno and Persani, Luca and Piras, Maria G. and Psaty, Bruce M. and Raikkonen, Katri and Richards, J. Brent and Rivadeneira, Fernando and Sala, Cinzia and Sabra, Mona M. and Sattar, Naveed and Shields, Beverley M. and Soranzo, Nicole and Starr, John M. and Stott, David J. and Sweep, Fred C. G. J. and Usala, Gianluca and van der Klauw, Melanie M. and van Heemst, Diana and van Mullem, Alies and Vermeulen, Sita H. and Visser, W. Edward and Walsh, John P. and Westendorp, Rudi G. J. and Widen, Elisabeth and Zhai, Guangju and Cucca, Francesco and Deary, Ian J. and Eriksson, Johan G. and Ferrucci, Luigi and Fox, Caroline S. and Jukema, J. Wouter and Kiemeney, Lambertus A. and Pramstaller, Peter P. and Schlessinger, David and Shuldiner, Alan R. and Slagboom, Eline P. and Uitterlinden, Andre G. and Vaidya, Bijay and Visser, Theo J. and Wolffenbuttel, Bruce H. R. and Meulenbelt, Ingrid and Rotter, Jerome I. and Spector, Tim D. and Hicks, Andrew A. and Toniolo, Daniela and Sanna, Serena and Peeters, Robin P. and Naitza, Silvia}, doi = {10.1371/journal.pgen.1003266}, issn = {1553-7404 1553-7390}, year = {2013}, date = {2013-01-01}, journal = {PLoS Genet}, volume = {9}, number = {2}, pages = {e1003266}, abstract = {Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. |
Pippucci, Tommaso ; Parmeggiani, Antonia ; Palombo, Flavia ; Maresca, Alessandra ; Angius, Andrea ; Crisponi, Laura ; Cucca, Francesco ; Liguori, Rocco ; Valentino, Maria Lucia ; Seri, Marco ; Carelli, Valerio A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. Journal Article PLoS One, 8 (12), pp. e82154, 2013, ISSN: 1932-6203 1932-6203. @article{pippucci_novel_2013, title = {A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy.}, author = {Pippucci, Tommaso and Parmeggiani, Antonia and Palombo, Flavia and Maresca, Alessandra and Angius, Andrea and Crisponi, Laura and Cucca, Francesco and Liguori, Rocco and Valentino, Maria Lucia and Seri, Marco and Carelli, Valerio}, doi = {10.1371/journal.pone.0082154}, issn = {1932-6203 1932-6203}, year = {2013}, date = {2013-01-01}, journal = {PLoS One}, volume = {8}, number = {12}, pages = {e82154}, abstract = {Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding alpha2delta-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished alpha2delta-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding alpha2delta-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished alpha2delta-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental. |
Elhaik, Eran ; Greenspan, Elliott ; Staats, Sean ; Krahn, Thomas ; Tyler-Smith, Chris ; Xue, Yali ; Tofanelli, Sergio ; Francalacci, Paolo ; Cucca, Francesco ; Pagani, Luca ; Jin, Li ; Li, Hui ; Schurr, Theodore G; Greenspan, Bennett ; Spencer Wells, R The GenoChip: a new tool for genetic anthropology. Journal Article Genome Biol Evol, 5 (5), pp. 1021–1031, 2013, ISSN: 1759-6653 1759-6653. @article{elhaik_genochip:_2013, title = {The GenoChip: a new tool for genetic anthropology.}, author = {Elhaik, Eran and Greenspan, Elliott and Staats, Sean and Krahn, Thomas and Tyler-Smith, Chris and Xue, Yali and Tofanelli, Sergio and Francalacci, Paolo and Cucca, Francesco and Pagani, Luca and Jin, Li and Li, Hui and Schurr, Theodore G. and Greenspan, Bennett and Spencer Wells, R.}, doi = {10.1093/gbe/evt066}, issn = {1759-6653 1759-6653}, year = {2013}, date = {2013-01-01}, journal = {Genome Biol Evol}, volume = {5}, number = {5}, pages = {1021--1031}, abstract = {The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project's new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. The GenoChip includes ancestry informative markers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all known Y-chromosome and mtDNA haplogroups. The chip was carefully vetted to avoid inclusion of medically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPs without any known health, medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project's new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. The GenoChip includes ancestry informative markers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all known Y-chromosome and mtDNA haplogroups. The chip was carefully vetted to avoid inclusion of medically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPs without any known health, medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics. |
van der Loos, Matthijs J H M; Rietveld, Cornelius A; Eklund, Niina ; Koellinger, Philipp D; Rivadeneira, Fernando ; Abecasis, Goncalo R; Ankra-Badu, Georgina A; Baumeister, Sebastian E; Benjamin, Daniel J; Biffar, Reiner ; Blankenberg, Stefan ; Boomsma, Dorret I; Cesarini, David ; Cucca, Francesco ; de Geus, Eco J C; Dedoussis, George ; Deloukas, Panos ; Dimitriou, Maria ; Eiriksdottir, Guethny ; Eriksson, Johan ; Gieger, Christian ; Gudnason, Vilmundur ; Hohne, Birgit ; Holle, Rolf ; Hottenga, Jouke-Jan ; Isaacs, Aaron ; Jarvelin, Marjo-Riitta ; Johannesson, Magnus ; Kaakinen, Marika ; Kahonen, Mika ; Kanoni, Stavroula ; Laaksonen, Maarit A; Lahti, Jari ; Launer, Lenore J; Lehtimaki, Terho ; Loitfelder, Marisa ; Magnusson, Patrik K E; Naitza, Silvia ; Oostra, Ben A; Perola, Markus ; Petrovic, Katja ; Quaye, Lydia ; Raitakari, Olli ; Ripatti, Samuli ; Scheet, Paul ; Schlessinger, David ; Schmidt, Carsten O; Schmidt, Helena ; Schmidt, Reinhold ; Senft, Andrea ; Smith, Albert V; Spector, Timothy D; Surakka, Ida ; Svento, Rauli ; Terracciano, Antonio ; Tikkanen, Emmi ; van Duijn, Cornelia M; Viikari, Jorma ; Volzke, Henry ; Wichmann, H.-Erich ; Wild, Philipp S; Willems, Sara M; Willemsen, Gonneke ; van Rooij, Frank J A; Groenen, Patrick J F; Uitterlinden, Andre G; Hofman, Albert ; Thurik, Roy A The molecular genetic architecture of self-employment. Journal Article PLoS One, 8 (4), pp. e60542, 2013, ISSN: 1932-6203 1932-6203. @article{van_der_loos_molecular_2013, title = {The molecular genetic architecture of self-employment.}, author = {van der Loos, Matthijs J. H. M. and Rietveld, Cornelius A. and Eklund, Niina and Koellinger, Philipp D. and Rivadeneira, Fernando and Abecasis, Goncalo R. and Ankra-Badu, Georgina A. and Baumeister, Sebastian E. and Benjamin, Daniel J. and Biffar, Reiner and Blankenberg, Stefan and Boomsma, Dorret I. and Cesarini, David and Cucca, Francesco and de Geus, Eco J. C. and Dedoussis, George and Deloukas, Panos and Dimitriou, Maria and Eiriksdottir, Guethny and Eriksson, Johan and Gieger, Christian and Gudnason, Vilmundur and Hohne, Birgit and Holle, Rolf and Hottenga, Jouke-Jan and Isaacs, Aaron and Jarvelin, Marjo-Riitta and Johannesson, Magnus and Kaakinen, Marika and Kahonen, Mika and Kanoni, Stavroula and Laaksonen, Maarit A. and Lahti, Jari and Launer, Lenore J. and Lehtimaki, Terho and Loitfelder, Marisa and Magnusson, Patrik K. E. and Naitza, Silvia and Oostra, Ben A. and Perola, Markus and Petrovic, Katja and Quaye, Lydia and Raitakari, Olli and Ripatti, Samuli and Scheet, Paul and Schlessinger, David and Schmidt, Carsten O. and Schmidt, Helena and Schmidt, Reinhold and Senft, Andrea and Smith, Albert V. and Spector, Timothy D. and Surakka, Ida and Svento, Rauli and Terracciano, Antonio and Tikkanen, Emmi and van Duijn, Cornelia M. and Viikari, Jorma and Volzke, Henry and Wichmann, H.-Erich and Wild, Philipp S. and Willems, Sara M. and Willemsen, Gonneke and van Rooij, Frank J. A. and Groenen, Patrick J. F. and Uitterlinden, Andre G. and Hofman, Albert and Thurik, A. Roy}, doi = {10.1371/journal.pone.0060542}, issn = {1932-6203 1932-6203}, year = {2013}, date = {2013-01-01}, journal = {PLoS One}, volume = {8}, number = {4}, pages = {e60542}, abstract = {Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (sigma(g)(2)/sigma(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with ptextless10(-5) were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (ptextgreater/=0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (sigma(g)(2)/sigma(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with ptextless10(-5) were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (ptextgreater/=0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases. |
Rietveld, Cornelius A; Medland, Sarah E; Derringer, Jaime ; Yang, Jian ; Esko, Tonu ; Martin, Nicolas W; Westra, Harm-Jan ; Shakhbazov, Konstantin ; [...], ; Cucca, Francesco ; de Andrade, Mariza ; De Jager, Philip L; De Neve, Jan-Emmanuel ; Deary, Ian J; Dedoussis, George V; Deloukas, Panos ; Dimitriou, Maria ; Eiriksdottir, Guethny ; Elderson, Martin F; Eriksson, Johan G; Evans, David M; Faul, Jessica D; Ferrucci, Luigi ; Garcia, Melissa E; Gronberg, Henrik ; Guethnason, Vilmundur ; Hall, Per ; Harris, Juliette M; Harris, Tamara B; Hastie, Nicholas D; Heath, Andrew C; Hernandez, Dena G; Hoffmann, Wolfgang ; Hofman, Adriaan ; Holle, Rolf ; Holliday, Elizabeth G; Hottenga, Jouke-Jan ; Iacono, William G; Illig, Thomas ; Jarvelin, Marjo-Riitta ; Kahonen, Mika ; Kaprio, Jaakko ; Kirkpatrick, Robert M; Kowgier, Matthew ; Latvala, Antti ; Launer, Lenore J; Lawlor, Debbie A; Lehtimaki, Terho ; Li, Jingmei ; Lichtenstein, Paul ; Lichtner, Peter ; Liewald, David C; Madden, Pamela A; Magnusson, Patrik K E; Makinen, Tomi E; Masala, Marco ; McGue, Matt ; Metspalu, Andres ; Mielck, Andreas ; Miller, Michael B; Montgomery, Grant W; Mukherjee, Sutapa ; Nyholt, Dale R; Oostra, Ben A; Palmer, Lyle J; Palotie, Aarno ; Penninx, Brenda W J H; Perola, Markus ; Peyser, Patricia A; Preisig, Martin ; Raikkonen, Katri ; Raitakari, Olli T; Realo, Anu ; Ring, Susan M; Ripatti, Samuli ; Rivadeneira, Fernando ; Rudan, Igor ; Rustichini, Aldo ; Salomaa, Veikko ; Sarin, Antti-Pekka ; Schlessinger, David ; Scott, Rodney J; Snieder, Harold ; St Pourcain, Beate ; Starr, John M; Sul, Jae Hoon ; Surakka, Ida ; Svento, Rauli ; Teumer, Alexander ; Tiemeier, Henning ; van Rooij, Frank J A; Van Wagoner, David R; Vartiainen, Erkki ; Viikari, Jorma ; Vollenweider, Peter ; Vonk, Judith M; Waeber, Gerard ; Weir, David R; Wichmann, H.-Erich ; Widen, Elisabeth ; Willemsen, Gonneke ; Wilson, James F; Wright, Alan F; Conley, Dalton ; Davey-Smith, George ; Franke, Lude ; Groenen, Patrick J F; Hofman, Albert ; Johannesson, Magnus ; Kardia, Sharon L R; Krueger, Robert F; Laibson, David ; Martin, Nicholas G; Meyer, Michelle N; Posthuma, Danielle ; Thurik, Roy A; Timpson, Nicholas J; Uitterlinden, Andre G; van Duijn, Cornelia M; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David ; Koellinger, Philipp D GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Journal Article Science, 340 (6139), pp. 1467–1471, 2013, ISSN: 1095-9203 0036-8075. @article{rietveld_gwas_2013, title = {GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.}, author = {Rietveld, Cornelius A. and Medland, Sarah E. and Derringer, Jaime and Yang, Jian and Esko, Tonu and Martin, Nicolas W. and Westra, Harm-Jan and Shakhbazov, Konstantin and [...] and Cucca, Francesco and de Andrade, Mariza and De Jager, Philip L. and De Neve, Jan-Emmanuel and Deary, Ian J. and Dedoussis, George V. and Deloukas, Panos and Dimitriou, Maria and Eiriksdottir, Guethny and Elderson, Martin F. and Eriksson, Johan G. and Evans, David M. and Faul, Jessica D. and Ferrucci, Luigi and Garcia, Melissa E. and Gronberg, Henrik and Guethnason, Vilmundur and Hall, Per and Harris, Juliette M. and Harris, Tamara B. and Hastie, Nicholas D. and Heath, Andrew C. and Hernandez, Dena G. and Hoffmann, Wolfgang and Hofman, Adriaan and Holle, Rolf and Holliday, Elizabeth G. and Hottenga, Jouke-Jan and Iacono, William G. and Illig, Thomas and Jarvelin, Marjo-Riitta and Kahonen, Mika and Kaprio, Jaakko and Kirkpatrick, Robert M. and Kowgier, Matthew and Latvala, Antti and Launer, Lenore J. and Lawlor, Debbie A. and Lehtimaki, Terho and Li, Jingmei and Lichtenstein, Paul and Lichtner, Peter and Liewald, David C. and Madden, Pamela A. and Magnusson, Patrik K. E. and Makinen, Tomi E. and Masala, Marco and McGue, Matt and Metspalu, Andres and Mielck, Andreas and Miller, Michael B. and Montgomery, Grant W. and Mukherjee, Sutapa and Nyholt, Dale R. and Oostra, Ben A. and Palmer, Lyle J. and Palotie, Aarno and Penninx, Brenda W. J. H. and Perola, Markus and Peyser, Patricia A. and Preisig, Martin and Raikkonen, Katri and Raitakari, Olli T. and Realo, Anu and Ring, Susan M. and Ripatti, Samuli and Rivadeneira, Fernando and Rudan, Igor and Rustichini, Aldo and Salomaa, Veikko and Sarin, Antti-Pekka and Schlessinger, David and Scott, Rodney J. and Snieder, Harold and St Pourcain, Beate and Starr, John M. and Sul, Jae Hoon and Surakka, Ida and Svento, Rauli and Teumer, Alexander and Tiemeier, Henning and van Rooij, Frank J. A. and Van Wagoner, David R. and Vartiainen, Erkki and Viikari, Jorma and Vollenweider, Peter and Vonk, Judith M. and Waeber, Gerard and Weir, David R. and Wichmann, H.-Erich and Widen, Elisabeth and Willemsen, Gonneke and Wilson, James F. and Wright, Alan F. and Conley, Dalton and Davey-Smith, George and Franke, Lude and Groenen, Patrick J. F. and Hofman, Albert and Johannesson, Magnus and Kardia, Sharon L. R. and Krueger, Robert F. and Laibson, David and Martin, Nicholas G. and Meyer, Michelle N. and Posthuma, Danielle and Thurik, A. Roy and Timpson, Nicholas J. and Uitterlinden, Andre G. and van Duijn, Cornelia M. and Visscher, Peter M. and Benjamin, Daniel J. and Cesarini, David and Koellinger, Philipp D.}, doi = {10.1126/science.1235488}, issn = {1095-9203 0036-8075}, year = {2013}, date = {2013-01-01}, journal = {Science}, volume = {340}, number = {6139}, pages = {1467--1471}, abstract = {A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) approximately 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximately 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) approximately 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximately 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. |
2012 |
Fozza, Claudio ; Contini, Salvatore ; Corda, Giovanna ; Virdis, Patrizia ; Galleu, Antonio ; Bonfigli, Silvana ; Pacifico, Adolfo ; Maioli, Mario ; Mastinu, Francesco ; Pitzalis, Maristella ; Cucca, Francesco ; Longinotti, Maurizio T-cell receptor repertoire analysis in monozygotic twins concordant and discordant for type 1 diabetes. Journal Article Immunobiology, 217 (9), pp. 920–925, 2012, ISSN: 1878-3279 0171-2985. @article{fozza_t-cell_2012, title = {T-cell receptor repertoire analysis in monozygotic twins concordant and discordant for type 1 diabetes.}, author = {Fozza, Claudio and Contini, Salvatore and Corda, Giovanna and Virdis, Patrizia and Galleu, Antonio and Bonfigli, Silvana and Pacifico, Adolfo and Maioli, Mario and Mastinu, Francesco and Pitzalis, Maristella and Cucca, Francesco and Longinotti, Maurizio}, doi = {10.1016/j.imbio.2012.01.002}, issn = {1878-3279 0171-2985}, year = {2012}, date = {2012-09-01}, journal = {Immunobiology}, volume = {217}, number = {9}, pages = {920--925}, abstract = {Several data suggest that stochastic rearrangements of the TCR could play a pathogenic role in both disease predisposition and protection in type 1 diabetes (T1D). As twin sets offer an enormous potential in evaluating the role of genetic and environmental factors in susceptibility to disease, the main goal of this study was to assess whether the degree of sharing of the expressed TCR repertoire of twin pairs discordant for T1D differs from that of disease concordant pairs. We performed our analysis in 5 pairs of monozygotic twins, 3 of which were concordant and 2 discordant for T1D, by combining flow cytometry and CDR3 spectratyping on both CD4+ and CD8+ T-cells. Our data show that TCR repertoires show increased level of concordance within each twin pair, especially in CD8+ cells, in terms of mean BV expression levels on flow cytometry as well as of CDR3 patterns and frequencies of skewed or oligoclonal BV subfamilies on spectratyping. It is worth noting that the degree of similarity among twins seems to be independent of concordance or discordance for T1D. Our findings seem to suggest that in monozygotic twins with T1D the TCR repertoire is influenced by genetic factors more than by the presence of the autoimmune disorder itself.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several data suggest that stochastic rearrangements of the TCR could play a pathogenic role in both disease predisposition and protection in type 1 diabetes (T1D). As twin sets offer an enormous potential in evaluating the role of genetic and environmental factors in susceptibility to disease, the main goal of this study was to assess whether the degree of sharing of the expressed TCR repertoire of twin pairs discordant for T1D differs from that of disease concordant pairs. We performed our analysis in 5 pairs of monozygotic twins, 3 of which were concordant and 2 discordant for T1D, by combining flow cytometry and CDR3 spectratyping on both CD4+ and CD8+ T-cells. Our data show that TCR repertoires show increased level of concordance within each twin pair, especially in CD8+ cells, in terms of mean BV expression levels on flow cytometry as well as of CDR3 patterns and frequencies of skewed or oligoclonal BV subfamilies on spectratyping. It is worth noting that the degree of similarity among twins seems to be independent of concordance or discordance for T1D. Our findings seem to suggest that in monozygotic twins with T1D the TCR repertoire is influenced by genetic factors more than by the presence of the autoimmune disorder itself. |
Cagliani, R; Guerini, F R; Fumagalli, M; Riva, S; Agliardi, C; Galimberti, D; Pozzoli, U; Goris, A; Dubois, B; Fenoglio, C; Forni, D; Sanna, S; Zara, I; Pitzalis, M; Zoledziewska, M; Cucca, F; Marini, F; Comi, G P; Scarpini, E; Bresolin, N; Clerici, M; Sironi, M A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis. Journal Article Mol Biol Evol, 29 (6), pp. 1599–1613, 2012, ISSN: 1537-1719 0737-4038. @article{cagliani_trans-specific_2012, title = {A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.}, author = {Cagliani, R. and Guerini, F. R. and Fumagalli, M. and Riva, S. and Agliardi, C. and Galimberti, D. and Pozzoli, U. and Goris, A. and Dubois, B. and Fenoglio, C. and Forni, D. and Sanna, S. and Zara, I. and Pitzalis, M. and Zoledziewska, M. and Cucca, F. and Marini, F. and Comi, G. P. and Scarpini, E. and Bresolin, N. and Clerici, M. and Sironi, M.}, doi = {10.1093/molbev/mss002}, issn = {1537-1719 0737-4038}, year = {2012}, date = {2012-06-01}, journal = {Mol Biol Evol}, volume = {29}, number = {6}, pages = {1599--1613}, abstract = {The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99}, keywords = {}, pubstate = {published}, tppubtype = {article} } The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99 |
Fozza, Claudio ; Zoledzieska, Magdalena ; Pitzalis, Maristella ; Simula, Maria Pina ; Galleu, Antonio ; Contini, Salvatore ; Bonfigli, Silvana ; Cucca, Francesco ; Longinotti, Maurizio TCRBV20S1 polymorphism does not influence the susceptibility to type 1 diabetes and multiple sclerosis in the Sardinian population. Journal Article Immunogenetics, 64 (2), pp. 153–154, 2012, ISSN: 1432-1211 0093-7711. @article{fozza_tcrbv20s1_2012, title = {TCRBV20S1 polymorphism does not influence the susceptibility to type 1 diabetes and multiple sclerosis in the Sardinian population.}, author = {Fozza, Claudio and Zoledzieska, Magdalena and Pitzalis, Maristella and Simula, Maria Pina and Galleu, Antonio and Contini, Salvatore and Bonfigli, Silvana and Cucca, Francesco and Longinotti, Maurizio}, doi = {10.1007/s00251-011-0575-z}, issn = {1432-1211 0093-7711}, year = {2012}, date = {2012-02-01}, journal = {Immunogenetics}, volume = {64}, number = {2}, pages = {153--154}, abstract = {Among the different T-cell receptor (TCR) BV20S1 polymorphisms, nucleotide substitution at position 524 results in the introduction of a stop codon, whose potential functional relevance is still unknown. We have recently showed in Sardinian subjects the most elevated allele frequency ever reported worldwide for this "null allele" (0.44). As this variant generates a gap in the TCR repertoire, this preliminary finding prompted us to further analyze the role of this polymorphism in the susceptibility to type 1 diabetes (T1D) and multiple sclerosis (MS), which are extremely common in this population. With this aim, we evaluated the influence of the TCRBV20S1 polymorphism by assessing it with the transmission disequilibirum test (TDT) in 652 T1D and 616 MS families, without detecting any significant difference. We conclude that the high frequency of this null allele in Sardinia is not directly related to the high incidence of these autoimmune diseases observed in this founder population.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Among the different T-cell receptor (TCR) BV20S1 polymorphisms, nucleotide substitution at position 524 results in the introduction of a stop codon, whose potential functional relevance is still unknown. We have recently showed in Sardinian subjects the most elevated allele frequency ever reported worldwide for this "null allele" (0.44). As this variant generates a gap in the TCR repertoire, this preliminary finding prompted us to further analyze the role of this polymorphism in the susceptibility to type 1 diabetes (T1D) and multiple sclerosis (MS), which are extremely common in this population. With this aim, we evaluated the influence of the TCRBV20S1 polymorphism by assessing it with the transmission disequilibirum test (TDT) in 652 T1D and 616 MS families, without detecting any significant difference. We conclude that the high frequency of this null allele in Sardinia is not directly related to the high incidence of these autoimmune diseases observed in this founder population. |
Naitza, Silvia ; Porcu, Eleonora ; Steri, Maristella ; Taub, Dennis D; Mulas, Antonella ; Xiao, Xiang ; Strait, James ; Dei, Mariano ; Lai, Sandra ; Busonero, Fabio ; Maschio, Andrea ; Usala, Gianluca ; Zoledziewska, Magdalena ; Sidore, Carlo ; Zara, Ilenia ; Pitzalis, Maristella ; Loi, Alessia ; Virdis, Francesca ; Piras, Roberta ; Deidda, Francesca ; Whalen, Michael B; Crisponi, Laura ; Concas, Antonio ; Podda, Carlo ; Uzzau, Sergio ; Scheet, Paul ; Longo, Dan L; Lakatta, Edward ; Abecasis, Gon{ç}alo R; Cao, Antonio ; Schlessinger, David ; Uda, Manuela ; Sanna, Serena ; Cucca, Francesco A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. Journal Article PLoS genetics, 8 (1), pp. e1002480, 2012, ISSN: 1553-7404. @article{Naitza2012, title = {A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.}, author = {Naitza, Silvia and Porcu, Eleonora and Steri, Maristella and Taub, Dennis D and Mulas, Antonella and Xiao, Xiang and Strait, James and Dei, Mariano and Lai, Sandra and Busonero, Fabio and Maschio, Andrea and Usala, Gianluca and Zoledziewska, Magdalena and Sidore, Carlo and Zara, Ilenia and Pitzalis, Maristella and Loi, Alessia and Virdis, Francesca and Piras, Roberta and Deidda, Francesca and Whalen, Michael B and Crisponi, Laura and Concas, Antonio and Podda, Carlo and Uzzau, Sergio and Scheet, Paul and Longo, Dan L and Lakatta, Edward and Abecasis, Gon{ç}alo R and Cao, Antonio and Schlessinger, David and Uda, Manuela and Sanna, Serena and Cucca, Francesco}, editor = {Sabeti, Pardis C.}, url = {http://dx.plos.org/10.1371/journal.pgen.1002480 http://www.ncbi.nlm.nih.gov/pubmed/22291609 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3266885}, doi = {10.1371/journal.pgen.1002480}, issn = {1553-7404}, year = {2012}, date = {2012-01-01}, journal = {PLoS genetics}, volume = {8}, number = {1}, pages = {e1002480}, abstract = {Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process. |
Li, Bingshan ; Chen, Wei ; Zhan, Xiaowei ; Busonero, Fabio ; Sanna, Serena ; Sidore, Carlo ; Cucca, Francesco ; Kang, Hyun M; Abecasis, Goncalo R A likelihood-based framework for variant calling and de novo mutation detection in families. Journal Article PLoS Genet, 8 (10), pp. e1002944, 2012, ISSN: 1553-7404 1553-7390. @article{li_likelihood-based_2012, title = {A likelihood-based framework for variant calling and de novo mutation detection in families.}, author = {Li, Bingshan and Chen, Wei and Zhan, Xiaowei and Busonero, Fabio and Sanna, Serena and Sidore, Carlo and Cucca, Francesco and Kang, Hyun M. and Abecasis, Goncalo R.}, doi = {10.1371/journal.pgen.1002944}, issn = {1553-7404 1553-7390}, year = {2012}, date = {2012-01-01}, journal = {PLoS Genet}, volume = {8}, number = {10}, pages = {e1002944}, abstract = {Family samples, which can be enriched for rare causal variants by focusing on families with multiple extreme individuals and which facilitate detection of de novo mutation events, provide an attractive resource for next-generation sequencing studies. Here, we describe, implement, and evaluate a likelihood-based framework for analysis of next generation sequence data in family samples. Our framework is able to identify variant sites accurately and to assign individual genotypes, and can handle de novo mutation events, increasing the sensitivity and specificity of variant calling and de novo mutation detection. Through simulations we show explicit modeling of family relationships is especially useful for analyses of low-frequency variants and that genotype accuracy increases with the number of individuals sequenced per family. Compared with the standard approach of ignoring relatedness, our methods identify and accurately genotype more variants, and have high specificity for detecting de novo mutation events. The improvement in accuracy using our methods over the standard approach is particularly pronounced for low-frequency variants. Furthermore the family-aware calling framework dramatically reduces Mendelian inconsistencies and is beneficial for family-based analysis. We hope our framework and software will facilitate continuing efforts to identify genetic factors underlying human diseases.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Family samples, which can be enriched for rare causal variants by focusing on families with multiple extreme individuals and which facilitate detection of de novo mutation events, provide an attractive resource for next-generation sequencing studies. Here, we describe, implement, and evaluate a likelihood-based framework for analysis of next generation sequence data in family samples. Our framework is able to identify variant sites accurately and to assign individual genotypes, and can handle de novo mutation events, increasing the sensitivity and specificity of variant calling and de novo mutation detection. Through simulations we show explicit modeling of family relationships is especially useful for analyses of low-frequency variants and that genotype accuracy increases with the number of individuals sequenced per family. Compared with the standard approach of ignoring relatedness, our methods identify and accurately genotype more variants, and have high specificity for detecting de novo mutation events. The improvement in accuracy using our methods over the standard approach is particularly pronounced for low-frequency variants. Furthermore the family-aware calling framework dramatically reduces Mendelian inconsistencies and is beneficial for family-based analysis. We hope our framework and software will facilitate continuing efforts to identify genetic factors underlying human diseases. |
Matesanz, Fuencisla ; Gonzalez-Perez, Antonio ; Lucas, Miguel ; Sanna, Serena ; Gayan, Javier ; Urcelay, Elena ; Zara, Ilenia ; Pitzalis, Maristella ; Cavanillas, Maria L; Arroyo, Rafael ; Zoledziewska, Magdalena ; Marrosu, Marisa ; Fernandez, Oscar ; Leyva, Laura ; Alcina, Antonio ; Fedetz, Maria ; Moreno-Rey, Concha ; Velasco, Juan ; Real, Luis M; Ruiz-Pena, Juan Luis ; Cucca, Francesco ; Ruiz, Agustin ; Izquierdo, Guillermo Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1. Journal Article PLoS One, 7 (5), pp. e36140, 2012, ISSN: 1932-6203 1932-6203. @article{matesanz_genome-wide_2012, title = {Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1.}, author = {Matesanz, Fuencisla and Gonzalez-Perez, Antonio and Lucas, Miguel and Sanna, Serena and Gayan, Javier and Urcelay, Elena and Zara, Ilenia and Pitzalis, Maristella and Cavanillas, Maria L. and Arroyo, Rafael and Zoledziewska, Magdalena and Marrosu, Marisa and Fernandez, Oscar and Leyva, Laura and Alcina, Antonio and Fedetz, Maria and Moreno-Rey, Concha and Velasco, Juan and Real, Luis M. and Ruiz-Pena, Juan Luis and Cucca, Francesco and Ruiz, Agustin and Izquierdo, Guillermo}, doi = {10.1371/journal.pone.0036140}, issn = {1932-6203 1932-6203}, year = {2012}, date = {2012-01-01}, journal = {PLoS One}, volume = {7}, number = {5}, pages = {e36140}, abstract = {Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 x 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 x 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS. |
Voight, Benjamin F; Kang, Hyun Min ; Ding, Jun ; Palmer, Cameron D; Sidore, Carlo ; Chines, Peter S; Burtt, Noel P; Fuchsberger, Christian ; Li, Yanming ; Erdmann, Jeanette ; Frayling, Timothy M; Heid, Iris M; Jackson, Anne U; Johnson, Toby ; Kilpelainen, Tuomas O; Lindgren, Cecilia M; Morris, Andrew P; Prokopenko, Inga ; Randall, Joshua C; Saxena, Richa ; Soranzo, Nicole ; Speliotes, Elizabeth K; Teslovich, Tanya M; Wheeler, Eleanor ; Maguire, Jared ; Parkin, Melissa ; Potter, Simon ; Rayner, William N; Robertson, Neil ; Stirrups, Kathleen ; Winckler, Wendy ; Sanna, Serena ; Mulas, Antonella ; Nagaraja, Ramaiah ; Cucca, Francesco ; Barroso, Ines ; Deloukas, Panos ; Loos, Ruth J F; Kathiresan, Sekar ; Munroe, Patricia B; Newton-Cheh, Christopher ; Pfeufer, Arne ; Samani, Nilesh J; Schunkert, Heribert ; Hirschhorn, Joel N; Altshuler, David ; McCarthy, Mark I; Abecasis, Goncalo R; Boehnke, Michael The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. Journal Article PLoS Genet, 8 (8), pp. e1002793, 2012, ISSN: 1553-7404 1553-7390. @article{voight_metabochip_2012, title = {The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits.}, author = {Voight, Benjamin F. and Kang, Hyun Min and Ding, Jun and Palmer, Cameron D. and Sidore, Carlo and Chines, Peter S. and Burtt, Noel P. and Fuchsberger, Christian and Li, Yanming and Erdmann, Jeanette and Frayling, Timothy M. and Heid, Iris M. and Jackson, Anne U. and Johnson, Toby and Kilpelainen, Tuomas O. and Lindgren, Cecilia M. and Morris, Andrew P. and Prokopenko, Inga and Randall, Joshua C. and Saxena, Richa and Soranzo, Nicole and Speliotes, Elizabeth K. and Teslovich, Tanya M. and Wheeler, Eleanor and Maguire, Jared and Parkin, Melissa and Potter, Simon and Rayner, N. William and Robertson, Neil and Stirrups, Kathleen and Winckler, Wendy and Sanna, Serena and Mulas, Antonella and Nagaraja, Ramaiah and Cucca, Francesco and Barroso, Ines and Deloukas, Panos and Loos, Ruth J. F. and Kathiresan, Sekar and Munroe, Patricia B. and Newton-Cheh, Christopher and Pfeufer, Arne and Samani, Nilesh J. and Schunkert, Heribert and Hirschhorn, Joel N. and Altshuler, David and McCarthy, Mark I. and Abecasis, Goncalo R. and Boehnke, Michael}, doi = {10.1371/journal.pgen.1002793}, issn = {1553-7404 1553-7390}, year = {2012}, date = {2012-01-01}, journal = {PLoS Genet}, volume = {8}, number = {8}, pages = {e1002793}, abstract = {Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits. |
2011 |
Hunt, Karen A; Smyth, Deborah J; Balschun, Tobias ; Ban, Maria ; Mistry, Vanisha ; Ahmad, Tariq ; Anand, Vidya ; Barrett, Jeffrey C; Bhaw-Rosun, Leena ; Bockett, Nicholas A; Brand, Oliver J; Brouwer, Elisabeth ; Concannon, Patrick ; Cooper, Jason D; Dias, Kerith-Rae M; van Diemen, Cleo C; Dubois, Patrick C; Edkins, Sarah ; Folster-Holst, Regina ; Fransen, Karin ; Glass, David N; Heap, Graham A R; Hofmann, Sylvia ; Huizinga, Tom W J; Hunt, Sarah ; Langford, Cordelia ; Lee, James ; Mansfield, John ; Marrosu, Maria Giovanna ; Mathew, Christopher G; Mein, Charles A; Muller-Quernheim, Joachim ; Nutland, Sarah ; Onengut-Gumuscu, Suna ; Ouwehand, Willem ; Pearce, Kerra ; Prescott, Natalie J; Posthumus, Marcel D; Potter, Simon ; Rosati, Giulio ; Sambrook, Jennifer ; Satsangi, Jack ; Schreiber, Stefan ; Shtir, Corina ; Simmonds, Matthew J; Sudman, Marc ; Thompson, Susan D; Toes, Rene ; Trynka, Gosia ; Vyse, Timothy J; Walker, Neil M; Weidinger, Stephan ; Zhernakova, Alexandra ; Zoledziewska, Magdalena ; Weersma, Rinse K; Gough, Stephen C L; Sawcer, Stephen ; Wijmenga, Cisca ; Parkes, Miles ; Cucca, Francesco ; Franke, Andre ; Deloukas, Panos ; Rich, Stephen S; Todd, John A; van Heel, David A Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Journal Article Nat Genet, 44 (1), pp. 3–5, 2011, ISSN: 1546-1718 1061-4036. @article{hunt_rare_2011, title = {Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry.}, author = {Hunt, Karen A. and Smyth, Deborah J. and Balschun, Tobias and Ban, Maria and Mistry, Vanisha and Ahmad, Tariq and Anand, Vidya and Barrett, Jeffrey C. and Bhaw-Rosun, Leena and Bockett, Nicholas A. and Brand, Oliver J. and Brouwer, Elisabeth and Concannon, Patrick and Cooper, Jason D. and Dias, Kerith-Rae M. and van Diemen, Cleo C. and Dubois, Patrick C. and Edkins, Sarah and Folster-Holst, Regina and Fransen, Karin and Glass, David N. and Heap, Graham A. R. and Hofmann, Sylvia and Huizinga, Tom W. J. and Hunt, Sarah and Langford, Cordelia and Lee, James and Mansfield, John and Marrosu, Maria Giovanna and Mathew, Christopher G. and Mein, Charles A. and Muller-Quernheim, Joachim and Nutland, Sarah and Onengut-Gumuscu, Suna and Ouwehand, Willem and Pearce, Kerra and Prescott, Natalie J. and Posthumus, Marcel D. and Potter, Simon and Rosati, Giulio and Sambrook, Jennifer and Satsangi, Jack and Schreiber, Stefan and Shtir, Corina and Simmonds, Matthew J. and Sudman, Marc and Thompson, Susan D. and Toes, Rene and Trynka, Gosia and Vyse, Timothy J. and Walker, Neil M. and Weidinger, Stephan and Zhernakova, Alexandra and Zoledziewska, Magdalena and Weersma, Rinse K. and Gough, Stephen C. L. and Sawcer, Stephen and Wijmenga, Cisca and Parkes, Miles and Cucca, Francesco and Franke, Andre and Deloukas, Panos and Rich, Stephen S. and Todd, John A. and van Heel, David A.}, doi = {10.1038/ng.1037}, issn = {1546-1718 1061-4036}, year = {2011}, date = {2011-12-01}, journal = {Nat Genet}, volume = {44}, number = {1}, pages = {3--5}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Chambers, John C; Zhang, Weihua ; Sehmi, Joban ; Li, Xinzhong ; Wass, Mark N; Van der Harst, Pim ; Holm, Hilma ; Sanna, Serena ; Kavousi, Maryam ; Baumeister, Sebastian E; Coin, Lachlan J; Deng, Guohong ; Gieger, Christian ; Heard-Costa, Nancy L; Hottenga, Jouke-Jan ; Kuhnel, Brigitte ; Kumar, Vinod ; Lagou, Vasiliki ; Liang, Liming ; Luan, Jian'an ; Vidal, Pedro Marques ; Mateo Leach, Irene ; O'Reilly, Paul F; Peden, John F; Rahmioglu, Nilufer ; Soininen, Pasi ; Speliotes, Elizabeth K; Yuan, Xin ; Thorleifsson, Gudmar ; Alizadeh, Behrooz Z; Atwood, Larry D; Borecki, Ingrid B; Brown, Morris J; Charoen, Pimphen ; Cucca, Francesco ; Das, Debashish ; de Geus, Eco J C; Dixon, Anna L; Doring, Angela ; Ehret, Georg ; Eyjolfsson, Gudmundur I; Farrall, Martin ; Forouhi, Nita G; Friedrich, Nele ; Goessling, Wolfram ; Gudbjartsson, Daniel F; Harris, Tamara B; Hartikainen, Anna-Liisa ; Heath, Simon ; Hirschfield, Gideon M; Hofman, Albert ; Homuth, Georg ; Hypponen, Elina ; Janssen, Harry L A; Johnson, Toby ; Kangas, Antti J; Kema, Ido P; Kuhn, Jens P; Lai, Sandra ; Lathrop, Mark ; Lerch, Markus M; Li, Yun ; Liang, Jake T; Lin, Jing-Ping ; Loos, Ruth J F; Martin, Nicholas G; Moffatt, Miriam F; Montgomery, Grant W; Munroe, Patricia B; Musunuru, Kiran ; Nakamura, Yusuke ; O'Donnell, Christopher J; Olafsson, Isleifur ; Penninx, Brenda W; Pouta, Anneli ; Prins, Bram P; Prokopenko, Inga ; Puls, Ralf ; Ruokonen, Aimo ; Savolainen, Markku J; Schlessinger, David ; Schouten, Jeoffrey N L; Seedorf, Udo ; Sen-Chowdhry, Srijita ; Siminovitch, Katherine A; Smit, Johannes H; Spector, Timothy D; Tan, Wenting ; Teslovich, Tanya M; Tukiainen, Taru ; Uitterlinden, Andre G; Van der Klauw, Melanie M; Vasan, Ramachandran S; Wallace, Chris ; Wallaschofski, Henri ; Wichmann, H.-Erich ; Willemsen, Gonneke ; Wurtz, Peter ; Xu, Chun ; Yerges-Armstrong, Laura M; Abecasis, Goncalo R; Ahmadi, Kourosh R; Boomsma, Dorret I; Caulfield, Mark ; Cookson, William O; van Duijn, Cornelia M; Froguel, Philippe ; Matsuda, Koichi ; McCarthy, Mark I; Meisinger, Christa ; Mooser, Vincent ; Pietilainen, Kirsi H; Schumann, Gunter ; Snieder, Harold ; Sternberg, Michael J E; Stolk, Ronald P; Thomas, Howard C; Thorsteinsdottir, Unnur ; Uda, Manuela ; Waeber, Gerard ; Wareham, Nicholas J; Waterworth, Dawn M; Watkins, Hugh ; Whitfield, John B; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Fox, Caroline S; Ala-Korpela, Mika ; Stefansson, Kari ; Vollenweider, Peter ; Volzke, Henry ; Schadt, Eric E; Scott, James ; Jarvelin, Marjo-Riitta ; Elliott, Paul ; Kooner, Jaspal S Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Journal Article Nat Genet, 43 (11), pp. 1131–1138, 2011, ISSN: 1546-1718 1061-4036. @article{chambers_genome-wide_2011, title = {Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.}, author = {Chambers, John C. and Zhang, Weihua and Sehmi, Joban and Li, Xinzhong and Wass, Mark N. and Van der Harst, Pim and Holm, Hilma and Sanna, Serena and Kavousi, Maryam and Baumeister, Sebastian E. and Coin, Lachlan J. and Deng, Guohong and Gieger, Christian and Heard-Costa, Nancy L. and Hottenga, Jouke-Jan and Kuhnel, Brigitte and Kumar, Vinod and Lagou, Vasiliki and Liang, Liming and Luan, Jian'an and Vidal, Pedro Marques and Mateo Leach, Irene and O'Reilly, Paul F. and Peden, John F. and Rahmioglu, Nilufer and Soininen, Pasi and Speliotes, Elizabeth K. and Yuan, Xin and Thorleifsson, Gudmar and Alizadeh, Behrooz Z. and Atwood, Larry D. and Borecki, Ingrid B. and Brown, Morris J. and Charoen, Pimphen and Cucca, Francesco and Das, Debashish and de Geus, Eco J. C. and Dixon, Anna L. and Doring, Angela and Ehret, Georg and Eyjolfsson, Gudmundur I. and Farrall, Martin and Forouhi, Nita G. and Friedrich, Nele and Goessling, Wolfram and Gudbjartsson, Daniel F. and Harris, Tamara B. and Hartikainen, Anna-Liisa and Heath, Simon and Hirschfield, Gideon M. and Hofman, Albert and Homuth, Georg and Hypponen, Elina and Janssen, Harry L. A. and Johnson, Toby and Kangas, Antti J. and Kema, Ido P. and Kuhn, Jens P. and Lai, Sandra and Lathrop, Mark and Lerch, Markus M. and Li, Yun and Liang, T. Jake and Lin, Jing-Ping and Loos, Ruth J. F. and Martin, Nicholas G. and Moffatt, Miriam F. and Montgomery, Grant W. and Munroe, Patricia B. and Musunuru, Kiran and Nakamura, Yusuke and O'Donnell, Christopher J. and Olafsson, Isleifur and Penninx, Brenda W. and Pouta, Anneli and Prins, Bram P. and Prokopenko, Inga and Puls, Ralf and Ruokonen, Aimo and Savolainen, Markku J. and Schlessinger, David and Schouten, Jeoffrey N. L. and Seedorf, Udo and Sen-Chowdhry, Srijita and Siminovitch, Katherine A. and Smit, Johannes H. and Spector, Timothy D. and Tan, Wenting and Teslovich, Tanya M. and Tukiainen, Taru and Uitterlinden, Andre G. and Van der Klauw, Melanie M. and Vasan, Ramachandran S. and Wallace, Chris and Wallaschofski, Henri and Wichmann, H.-Erich and Willemsen, Gonneke and Wurtz, Peter and Xu, Chun and Yerges-Armstrong, Laura M. and Abecasis, Goncalo R. and Ahmadi, Kourosh R. and Boomsma, Dorret I. and Caulfield, Mark and Cookson, William O. and van Duijn, Cornelia M. and Froguel, Philippe and Matsuda, Koichi and McCarthy, Mark I. and Meisinger, Christa and Mooser, Vincent and Pietilainen, Kirsi H. and Schumann, Gunter and Snieder, Harold and Sternberg, Michael J. E. and Stolk, Ronald P. and Thomas, Howard C. and Thorsteinsdottir, Unnur and Uda, Manuela and Waeber, Gerard and Wareham, Nicholas J. and Waterworth, Dawn M. and Watkins, Hugh and Whitfield, John B. and Witteman, Jacqueline C. M. and Wolffenbuttel, Bruce H. R. and Fox, Caroline S. and Ala-Korpela, Mika and Stefansson, Kari and Vollenweider, Peter and Volzke, Henry and Schadt, Eric E. and Scott, James and Jarvelin, Marjo-Riitta and Elliott, Paul and Kooner, Jaspal S.}, doi = {10.1038/ng.970}, issn = {1546-1718 1061-4036}, year = {2011}, date = {2011-10-01}, journal = {Nat Genet}, volume = {43}, number = {11}, pages = {1131--1138}, abstract = {Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. |
Terracciano, A; Esko, T; Sutin, A R; de Moor, M H M; Meirelles, O; Zhu, G; Tanaka, T; Giegling, I; Nutile, T; Realo, A; Allik, J; Hansell, N K; Wright, M J; Montgomery, G W; Willemsen, G; Hottenga, J -J; Friedl, M; Ruggiero, D; Sorice, R; Sanna, S; Cannas, A; Raikkonen, K; Widen, E; Palotie, A; Eriksson, J G; Cucca, F; Krueger, R F; Lahti, J; Luciano, M; Smoller, J W; van Duijn, C M; Abecasis, G R; Boomsma, D I; Ciullo, M; Costa, Jr P T; Ferrucci, L; Martin, N G; Metspalu, A; Rujescu, D; Schlessinger, D; Uda, M Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking. Journal Article Transl Psychiatry, 1 , pp. e49, 2011, ISSN: 2158-3188 2158-3188. @article{terracciano_meta-analysis_2011, title = {Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking.}, author = {Terracciano, A. and Esko, T. and Sutin, A. R. and de Moor, M. H. M. and Meirelles, O. and Zhu, G. and Tanaka, T. and Giegling, I. and Nutile, T. and Realo, A. and Allik, J. and Hansell, N. K. and Wright, M. J. and Montgomery, G. W. and Willemsen, G. and Hottenga, J.-J. and Friedl, M. and Ruggiero, D. and Sorice, R. and Sanna, S. and Cannas, A. and Raikkonen, K. and Widen, E. and Palotie, A. and Eriksson, J. G. and Cucca, F. and Krueger, R. F. and Lahti, J. and Luciano, M. and Smoller, J. W. and van Duijn, C. M. and Abecasis, G. R. and Boomsma, D. I. and Ciullo, M. and Costa, P. T. Jr and Ferrucci, L. and Martin, N. G. and Metspalu, A. and Rujescu, D. and Schlessinger, D. and Uda, M.}, doi = {10.1038/tp.2011.42}, issn = {2158-3188 2158-3188}, year = {2011}, date = {2011-10-01}, journal = {Transl Psychiatry}, volume = {1}, pages = {e49}, abstract = {The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 x 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed alpha-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 x 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed alpha-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders. |
Sanna, Serena ; Li, Bingshan ; Mulas, Antonella ; Sidore, Carlo ; Kang, Hyun M; Jackson, Anne U; Piras, Maria Grazia ; Usala, Gianluca ; Maninchedda, Giuseppe ; Sassu, Alessandro ; Serra, Fabrizio ; Palmas, Maria Antonietta ; Wood, William 3rd H; Njolstad, Inger ; Laakso, Markku ; Hveem, Kristian ; Tuomilehto, Jaakko ; Lakka, Timo A; Rauramaa, Rainer ; Boehnke, Michael ; Cucca, Francesco ; Uda, Manuela ; Schlessinger, David ; Nagaraja, Ramaiah ; Abecasis, Goncalo R Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. Journal Article PLoS Genet, 7 (7), pp. e1002198, 2011, ISSN: 1553-7404 1553-7390. @article{sanna_fine_2011, title = {Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.}, author = {Sanna, Serena and Li, Bingshan and Mulas, Antonella and Sidore, Carlo and Kang, Hyun M. and Jackson, Anne U. and Piras, Maria Grazia and Usala, Gianluca and Maninchedda, Giuseppe and Sassu, Alessandro and Serra, Fabrizio and Palmas, Maria Antonietta and Wood, William H. 3rd and Njolstad, Inger and Laakso, Markku and Hveem, Kristian and Tuomilehto, Jaakko and Lakka, Timo A. and Rauramaa, Rainer and Boehnke, Michael and Cucca, Francesco and Uda, Manuela and Schlessinger, David and Nagaraja, Ramaiah and Abecasis, Goncalo R.}, doi = {10.1371/journal.pgen.1002198}, issn = {1553-7404 1553-7390}, year = {2011}, date = {2011-07-01}, journal = {PLoS Genet}, volume = {7}, number = {7}, pages = {e1002198}, abstract = {Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of approximately 10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of approximately 10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. |
Fozza, Claudio ; Poddie, Fausto ; Contini, Salvatore ; Galleu, Antonio ; Cottoni, Francesca ; Longinotti, Maurizio ; Cucca, Francesco Keratitis-Ichthyosis-Deafness Syndrome, Atypical Connexin GJB2 Gene Mutation, and Peripheral Ŧ-Cell Lymphoma: More Than a Random Association? Journal Article Case Rep Hematol, 2011 , pp. 848461, 2011, ISSN: 2090-6579 2090-6579. @article{fozza_keratitis-ichthyosis-deafness_2011, title = {Keratitis-Ichthyosis-Deafness Syndrome, Atypical Connexin GJB2 Gene Mutation, and Peripheral Ŧ-Cell Lymphoma: More Than a Random Association?}, author = {Fozza, Claudio and Poddie, Fausto and Contini, Salvatore and Galleu, Antonio and Cottoni, Francesca and Longinotti, Maurizio and Cucca, Francesco}, doi = {10.1155/2011/848461}, issn = {2090-6579 2090-6579}, year = {2011}, date = {2011-01-01}, journal = {Case Rep Hematol}, volume = {2011}, pages = {848461}, abstract = {Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by skin lesions, neurosensorial hypoacusia, and keratitis, usually due to the c.148G --textgreater A mutation involving the connexin 26 gene. We report on a KID patient who showed the atypical c.101T --textgreater C mutation and developed a T-cell lymphoma so far never described in this group of patients.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by skin lesions, neurosensorial hypoacusia, and keratitis, usually due to the c.148G --textgreater A mutation involving the connexin 26 gene. We report on a KID patient who showed the atypical c.101T --textgreater C mutation and developed a T-cell lymphoma so far never described in this group of patients. |
2010 |
Sanna, Serena ; Pitzalis, Maristella ; Zoledziewska, Magdalena ; Zara, Ilenia ; Sidore, Carlo ; Murru, Raffaele ; Whalen, Michael B; Busonero, Fabio ; Maschio, Andrea ; Costa, Gianna ; Melis, Maria Cristina ; Deidda, Francesca ; Poddie, Fausto ; Morelli, Laura ; Farina, Gabriele ; Li, Yun ; Dei, Mariano ; Lai, Sandra ; Mulas, Antonella ; Cuccuru, Gianmauro ; Porcu, Eleonora ; Liang, Liming ; Zavattari, Patrizia ; Moi, Loredana ; Deriu, Elisa ; Urru, Francesca M; Bajorek, Michele ; Satta, Maria Anna ; Cocco, Eleonora ; Ferrigno, Paola ; Sotgiu, Stefano ; Pugliatti, Maura ; Traccis, Sebastiano ; Angius, Andrea ; Melis, Maurizio ; Rosati, Giulio ; Abecasis, Gon{ç}alo R; Uda, Manuela ; Marrosu, Maria Giovanna ; Schlessinger, David ; Cucca, Francesco Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis. Journal Article Nature genetics, 42 (6), pp. 495–7, 2010, ISSN: 1546-1718. @article{Sanna2010, title = {Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis.}, author = {Sanna, Serena and Pitzalis, Maristella and Zoledziewska, Magdalena and Zara, Ilenia and Sidore, Carlo and Murru, Raffaele and Whalen, Michael B and Busonero, Fabio and Maschio, Andrea and Costa, Gianna and Melis, Maria Cristina and Deidda, Francesca and Poddie, Fausto and Morelli, Laura and Farina, Gabriele and Li, Yun and Dei, Mariano and Lai, Sandra and Mulas, Antonella and Cuccuru, Gianmauro and Porcu, Eleonora and Liang, Liming and Zavattari, Patrizia and Moi, Loredana and Deriu, Elisa and Urru, M Francesca and Bajorek, Michele and Satta, Maria Anna and Cocco, Eleonora and Ferrigno, Paola and Sotgiu, Stefano and Pugliatti, Maura and Traccis, Sebastiano and Angius, Andrea and Melis, Maurizio and Rosati, Giulio and Abecasis, Gon{ç}alo R and Uda, Manuela and Marrosu, Maria Giovanna and Schlessinger, David and Cucca, Francesco}, url = {http://www.nature.com/doifinder/10.1038/ng.584 http://www.ncbi.nlm.nih.gov/pubmed/20453840 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3786343}, doi = {10.1038/ng.584}, issn = {1546-1718}, year = {2010}, date = {2010-06-01}, journal = {Nature genetics}, volume = {42}, number = {6}, pages = {495--7}, abstract = {A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10)}, keywords = {}, pubstate = {published}, tppubtype = {article} } A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10) |
Morelli, Laura ; Contu, Daniela ; Santoni, Federico ; Whalen, Michael B; Francalacci, Paolo ; Cucca, Francesco A comparison of Y-chromosome variation in Sardinia and Anatolia is more consistent with cultural rather than demic diffusion of agriculture. Journal Article PLoS One, 5 (4), pp. e10419, 2010, ISSN: 1932-6203 1932-6203. @article{morelli_comparison_2010, title = {A comparison of Y-chromosome variation in Sardinia and Anatolia is more consistent with cultural rather than demic diffusion of agriculture.}, author = {Morelli, Laura and Contu, Daniela and Santoni, Federico and Whalen, Michael B. and Francalacci, Paolo and Cucca, Francesco}, doi = {10.1371/journal.pone.0010419}, issn = {1932-6203 1932-6203}, year = {2010}, date = {2010-04-01}, journal = {PLoS One}, volume = {5}, number = {4}, pages = {e10419}, abstract = {Two alternative models have been proposed to explain the spread of agriculture in Europe during the Neolithic period. The demic diffusion model postulates the spreading of farmers from the Middle East along a Southeast to Northeast axis. Conversely, the cultural diffusion model assumes transmission of agricultural techniques without substantial movements of people. Support for the demic model derives largely from the observation of frequency gradients among some genetic variants, in particular haplogroups defined by single nucleotide polymorphisms (SNPs) in the Y-chromosome. A recent network analysis of the R-M269 Y chromosome lineage has purportedly corroborated Neolithic expansion from Anatolia, the site of diffusion of agriculture. However, the data are still controversial and the analyses so far performed are prone to a number of biases. In the present study we show that the addition of a single marker, DYSA7.2, dramatically changes the shape of the R-M269 network into a topology showing a clear Western-Eastern dichotomy not consistent with a radial diffusion of people from the Middle East. We have also assessed other Y-chromosome haplogroups proposed to be markers of the Neolithic diffusion of farmers and compared their intra-lineage variation--defined by short tandem repeats (STRs)--in Anatolia and in Sardinia, the only Western population where these lineages are present at appreciable frequencies and where there is substantial archaeological and genetic evidence of pre-Neolithic human occupation. The data indicate that Sardinia does not contain a subset of the variability present in Anatolia and that the shared variability between these populations is best explained by an earlier, pre-Neolithic dispersal of haplogroups from a common ancestral gene pool. Overall, these results are consistent with the cultural diffusion and do not support the demic model of agriculture diffusion.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Two alternative models have been proposed to explain the spread of agriculture in Europe during the Neolithic period. The demic diffusion model postulates the spreading of farmers from the Middle East along a Southeast to Northeast axis. Conversely, the cultural diffusion model assumes transmission of agricultural techniques without substantial movements of people. Support for the demic model derives largely from the observation of frequency gradients among some genetic variants, in particular haplogroups defined by single nucleotide polymorphisms (SNPs) in the Y-chromosome. A recent network analysis of the R-M269 Y chromosome lineage has purportedly corroborated Neolithic expansion from Anatolia, the site of diffusion of agriculture. However, the data are still controversial and the analyses so far performed are prone to a number of biases. In the present study we show that the addition of a single marker, DYSA7.2, dramatically changes the shape of the R-M269 network into a topology showing a clear Western-Eastern dichotomy not consistent with a radial diffusion of people from the Middle East. We have also assessed other Y-chromosome haplogroups proposed to be markers of the Neolithic diffusion of farmers and compared their intra-lineage variation--defined by short tandem repeats (STRs)--in Anatolia and in Sardinia, the only Western population where these lineages are present at appreciable frequencies and where there is substantial archaeological and genetic evidence of pre-Neolithic human occupation. The data indicate that Sardinia does not contain a subset of the variability present in Anatolia and that the shared variability between these populations is best explained by an earlier, pre-Neolithic dispersal of haplogroups from a common ancestral gene pool. Overall, these results are consistent with the cultural diffusion and do not support the demic model of agriculture diffusion. |
Maioli, M; Pes, G M; Delitala, G; Puddu, L; Falorni, A; Tolu, F; Lampis, R; Orru, V; Secchi, G; Cicalo, A M; Floris, R; Madau, G F; Pilosu, R M; Whalen, M; Cucca, F Eur J Endocrinol, 163 (4), pp. 541–549, 2010, ISSN: 1479-683X 0804-4643. @article{maioli_number_2010, title = {Number of autoantibodies and HLA genotype, more than high titers of glutamic acid decarboxylase autoantibodies, predict insulin dependence in latent autoimmune diabetes of adults.}, author = {Maioli, M. and Pes, G. M. and Delitala, G. and Puddu, L. and Falorni, A. and Tolu, F. and Lampis, R. and Orru, V. and Secchi, G. and Cicalo, A. M. and Floris, R. and Madau, G. F. and Pilosu, R. M. and Whalen, M. and Cucca, F.}, doi = {10.1530/EJE-10-0427}, issn = {1479-683X 0804-4643}, year = {2010}, date = {2010-01-01}, journal = {Eur J Endocrinol}, volume = {163}, number = {4}, pages = {541--549}, abstract = {OBJECTIVE: In latent autoimmune diabetes of adults (LADA), the progression into insulin-dependent diabetes is usually faster than in type 2 diabetes (T2D) but the factors influencing this progression are not completely known. In this study, we searched for sensitive markers associated with early development of insulin dependence. DESIGN: The screening of 5568 T2D patients for glutamic acid decarboxylase autoantibodies (GAD65Ab) identified 276 LADA patients (M=131; F=145) and in 251 of them, tyrosine phosphatase-2 (IA-2Ab) and thyroperoxidase autoantibodies (TPOAbs), some clinical features and genotype variation of the main type 1 diabetes (T1D) disease susceptibility loci (HLA-DRB1 and HLA-DQB1) were analyzed. RESULTS: Four years after the diagnosis of diabetes, high GAD65Ab titer was not significantly associated with faster progression toward insulin deficiency (P=0.104). Patients with GAD65Ab and TPOAb or IA-2Ab or triple positivity for both islet and TPOAbs (GAD65Ab/IA-2Ab/TPOAb) showed a significantly faster disease progression (P=0.002). Among 104 TPOAb-positive LADA patients, 10 received replacement therapy (l-thyroxine), 43 showed high TSH levels (62.7% developed insulin dependence), and 3 had hyperthyroidism treated with methimazole. Multivariate analysis revealed a significant effect on disease progression only for TPOAb (P=0.022), female gender (P=0.036), low body mass index (BMI; P=0.001), and T1D high/intermediate risk HLA-DRB1/DQB1 genotypes grouped (P=0.020). CONCLUSIONS: High GAD65Ab titers per se are not a major risk factor for disease progression in LADA, while the number of positive autoantibodies and HLA DRB1-DQB1 genotypes at high risk for T1D are significant predictors. Moreover, clinical characteristics such as low BMI and female gender are more likely to identify patients who will require insulin therapy within 4 years of diagnosis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: In latent autoimmune diabetes of adults (LADA), the progression into insulin-dependent diabetes is usually faster than in type 2 diabetes (T2D) but the factors influencing this progression are not completely known. In this study, we searched for sensitive markers associated with early development of insulin dependence. DESIGN: The screening of 5568 T2D patients for glutamic acid decarboxylase autoantibodies (GAD65Ab) identified 276 LADA patients (M=131; F=145) and in 251 of them, tyrosine phosphatase-2 (IA-2Ab) and thyroperoxidase autoantibodies (TPOAbs), some clinical features and genotype variation of the main type 1 diabetes (T1D) disease susceptibility loci (HLA-DRB1 and HLA-DQB1) were analyzed. RESULTS: Four years after the diagnosis of diabetes, high GAD65Ab titer was not significantly associated with faster progression toward insulin deficiency (P=0.104). Patients with GAD65Ab and TPOAb or IA-2Ab or triple positivity for both islet and TPOAbs (GAD65Ab/IA-2Ab/TPOAb) showed a significantly faster disease progression (P=0.002). Among 104 TPOAb-positive LADA patients, 10 received replacement therapy (l-thyroxine), 43 showed high TSH levels (62.7% developed insulin dependence), and 3 had hyperthyroidism treated with methimazole. Multivariate analysis revealed a significant effect on disease progression only for TPOAb (P=0.022), female gender (P=0.036), low body mass index (BMI; P=0.001), and T1D high/intermediate risk HLA-DRB1/DQB1 genotypes grouped (P=0.020). CONCLUSIONS: High GAD65Ab titers per se are not a major risk factor for disease progression in LADA, while the number of positive autoantibodies and HLA DRB1-DQB1 genotypes at high risk for T1D are significant predictors. Moreover, clinical characteristics such as low BMI and female gender are more likely to identify patients who will require insulin therapy within 4 years of diagnosis. |
2009 |
Zoledziewska, M; Costa, G; Pitzalis, M; Cocco, E; Melis, C; Moi, L; Zavattari, P; Murru, R; Lampis, R; Morelli, L; Poddie, F; Frongia, P; Pusceddu, P; Bajorek, M; Marras, A; Satta, A M; Chessa, A; Pugliatti, M; Sotgiu, S; Whalen, M B; Rosati, G; Cucca, F; Marrosu, M G Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia. Journal Article Genes and immunity, 10 (1), pp. 15–7, 2009, ISSN: 1476-5470. @article{Zoledziewska2009, title = {Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.}, author = {Zoledziewska, M and Costa, G and Pitzalis, M and Cocco, E and Melis, C and Moi, L and Zavattari, P and Murru, R and Lampis, R and Morelli, L and Poddie, F and Frongia, P and Pusceddu, P and Bajorek, M and Marras, A and Satta, A M and Chessa, A and Pugliatti, M and Sotgiu, S and Whalen, M B and Rosati, G and Cucca, F and Marrosu, M G}, url = {http://www.nature.com/doifinder/10.1038/gene.2008.84 http://www.ncbi.nlm.nih.gov/pubmed/18946483}, doi = {10.1038/gene.2008.84}, issn = {1476-5470}, year = {2009}, date = {2009-01-01}, journal = {Genes and immunity}, volume = {10}, number = {1}, pages = {15--7}, abstract = {Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway. |
2008 |
Zoledziewska, Magdalena ; Perra, Chiara ; Orr{ù}, Valeria ; Moi, Loredana ; Frongia, Paola ; Congia, Mauro ; Bottini, Nunzio ; Cucca, Francesco Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes. Journal Article Diabetes, 57 (1), pp. 229–34, 2008, ISSN: 1939-327X. @article{Zoledziewska2008, title = {Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes.}, author = {Zoledziewska, Magdalena and Perra, Chiara and Orr{ù}, Valeria and Moi, Loredana and Frongia, Paola and Congia, Mauro and Bottini, Nunzio and Cucca, Francesco}, url = {http://diabetes.diabetesjournals.org/cgi/doi/10.2337/db07-0289 http://www.ncbi.nlm.nih.gov/pubmed/17934143}, doi = {10.2337/db07-0289}, issn = {1939-327X}, year = {2008}, date = {2008-01-01}, journal = {Diabetes}, volume = {57}, number = {1}, pages = {229--34}, abstract = {OBJECTIVE The minor allele of the nonsynonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is positively associated with type 1 diabetes and other autoimmune diseases. Genetic and functional data underline its causal effect, but some studies suggest that this polymorphism does not entirely explain disease association of the PTPN22 region. The aim of this study was to evaluate type 1 diabetes association within this gene in the Sardinian population. RESEARCH DESIGN AND METHODS We resequenced the exons and potentially relevant portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 deletion insertion polymorphism [DIP]), 8 of which were novel. A representative set of 14 SNPs and the DIP were sequentially genotyped and assessed for disease association in 794 families, 490 sporadic patients, and 721 matched control subjects. RESULTS The +1858C>T variant, albeit rare in the general Sardinian population (allele frequency 0.014), was positively associated with type 1 diabetes (P(one tail) = 3.7 x 10(-3)). In contrast, the background haplotype in which this mutation occurred was common (haplotype frequency 0.117) and neutrally associated with disease. We did not confirm disease associations reported in other populations for non +1858C>T variants (rs2488457, rs1310182, and rs3811021), although they were present in appreciable frequencies in Sardinia. Additional weak disease associations with rare variants were detected in the Sardinian families but not confirmed in independent case-control sample sets and are most likely spurious. CONCLUSIONS We provide further evidence that the +1858C>T polymorphism is primarily associated with type 1 diabetes and exclude major contributions from other purportedly relevant variants within this gene.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE The minor allele of the nonsynonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is positively associated with type 1 diabetes and other autoimmune diseases. Genetic and functional data underline its causal effect, but some studies suggest that this polymorphism does not entirely explain disease association of the PTPN22 region. The aim of this study was to evaluate type 1 diabetes association within this gene in the Sardinian population. RESEARCH DESIGN AND METHODS We resequenced the exons and potentially relevant portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 deletion insertion polymorphism [DIP]), 8 of which were novel. A representative set of 14 SNPs and the DIP were sequentially genotyped and assessed for disease association in 794 families, 490 sporadic patients, and 721 matched control subjects. RESULTS The +1858C>T variant, albeit rare in the general Sardinian population (allele frequency 0.014), was positively associated with type 1 diabetes (P(one tail) = 3.7 x 10(-3)). In contrast, the background haplotype in which this mutation occurred was common (haplotype frequency 0.117) and neutrally associated with disease. We did not confirm disease associations reported in other populations for non +1858C>T variants (rs2488457, rs1310182, and rs3811021), although they were present in appreciable frequencies in Sardinia. Additional weak disease associations with rare variants were detected in the Sardinian families but not confirmed in independent case-control sample sets and are most likely spurious. CONCLUSIONS We provide further evidence that the +1858C>T polymorphism is primarily associated with type 1 diabetes and exclude major contributions from other purportedly relevant variants within this gene. |
Pitzalis, Maristella ; Zavattari, Patrizia ; Murru, Raffaele ; Deidda, Elisabetta ; Zoledziewska, Magdalena ; Murru, Daniela ; Moi, Loredana ; Motzo, Costantino ; Orru, Valeria ; Costa, Gianna ; Solla, Elisabetta ; Fadda, Elisabetta ; Schirru, Lucia ; Melis, Maria Cristina ; Lai, Marina ; Mancosu, Cristina ; Tranquilli, Stefania ; Cuccu, Stefania ; Rolesu, Marcella ; Secci, Maria Antonietta ; Corongiu, Daniela ; Contu, Daniela ; Lampis, Rosanna ; Nucaro, Annalisa ; Pala, Gavino ; Pacifico, Adolfo ; Maioli, Mario ; Frongia, Paola ; Chessa, Margherita ; Ricciardi, Rossella ; Lostia, Stanislao ; Marinaro, Anna Maria ; Milia, Anna Franca ; Landis, Novella ; Zedda, Maria Antonietta ; Whalen, Michael B; Santoni, Federico ; Marrosu, Maria Giovanna ; Devoto, Marcella ; Cucca, Francesco Genetic loci linked to type 1 diabetes and multiple sclerosis families in Sardinia. Journal Article BMC Med Genet, 9 , pp. 3, 2008, ISSN: 1471-2350 1471-2350. @article{pitzalis_genetic_2008, title = {Genetic loci linked to type 1 diabetes and multiple sclerosis families in Sardinia.}, author = {Pitzalis, Maristella and Zavattari, Patrizia and Murru, Raffaele and Deidda, Elisabetta and Zoledziewska, Magdalena and Murru, Daniela and Moi, Loredana and Motzo, Costantino and Orru, Valeria and Costa, Gianna and Solla, Elisabetta and Fadda, Elisabetta and Schirru, Lucia and Melis, Maria Cristina and Lai, Marina and Mancosu, Cristina and Tranquilli, Stefania and Cuccu, Stefania and Rolesu, Marcella and Secci, Maria Antonietta and Corongiu, Daniela and Contu, Daniela and Lampis, Rosanna and Nucaro, Annalisa and Pala, Gavino and Pacifico, Adolfo and Maioli, Mario and Frongia, Paola and Chessa, Margherita and Ricciardi, Rossella and Lostia, Stanislao and Marinaro, Anna Maria and Milia, Anna Franca and Landis, Novella and Zedda, Maria Antonietta and Whalen, Michael B. and Santoni, Federico and Marrosu, Maria Giovanna and Devoto, Marcella and Cucca, Francesco}, doi = {10.1186/1471-2350-9-3}, issn = {1471-2350 1471-2350}, year = {2008}, date = {2008-01-01}, journal = {BMC Med Genet}, volume = {9}, pages = {3}, abstract = {BACKGROUND: The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis. METHODS: To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic. RESULTS: In T1D, aside from the HLA locus, we found four regions showing a lod-score textgreater or =1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score textgreater or =1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD textgreater1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5). CONCLUSION: This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis. METHODS: To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic. RESULTS: In T1D, aside from the HLA locus, we found four regions showing a lod-score textgreater or =1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score textgreater or =1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD textgreater1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5). CONCLUSION: This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies. |
Contu, Daniela ; Morelli, Laura ; Santoni, Federico ; Foster, Jamie W; Francalacci, Paolo ; Cucca, Francesco PLoS One, 3 (1), pp. e1430, 2008, ISSN: 1932-6203 1932-6203. @article{contu_y-chromosome_2008, title = {Y-chromosome based evidence for pre-neolithic origin of the genetically homogeneous but diverse Sardinian population: inference for association scans.}, author = {Contu, Daniela and Morelli, Laura and Santoni, Federico and Foster, Jamie W. and Francalacci, Paolo and Cucca, Francesco}, doi = {10.1371/journal.pone.0001430}, issn = {1932-6203 1932-6203}, year = {2008}, date = {2008-01-01}, journal = {PLoS One}, volume = {3}, number = {1}, pages = {e1430}, abstract = {The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0-25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8-22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0-25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8-22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms. |
2007 |
Schirru, Enrico ; Corona, Valeria ; Usai-Satta, Paolo ; Scarpa, Maria ; Cucca, Francesco ; De Virgiliis, Stefano ; Rossino, Rossano ; Frau, Fulvia ; Macis, Maria Doloretta ; Jores, Rita-Desiree ; Congia, Mauro Decline of lactase activity and c/t-13910 variant in Sardinian childhood. Journal Article J Pediatr Gastroenterol Nutr, 45 (4), pp. 503–506, 2007, ISSN: 1536-4801 0277-2116. @article{schirru_decline_2007, title = {Decline of lactase activity and c/t-13910 variant in Sardinian childhood.}, author = {Schirru, Enrico and Corona, Valeria and Usai-Satta, Paolo and Scarpa, Maria and Cucca, Francesco and De Virgiliis, Stefano and Rossino, Rossano and Frau, Fulvia and Macis, Maria Doloretta and Jores, Rita-Desiree and Congia, Mauro}, doi = {10.1097/MPG.0b013e31805b5899}, issn = {1536-4801 0277-2116}, year = {2007}, date = {2007-10-01}, journal = {J Pediatr Gastroenterol Nutr}, volume = {45}, number = {4}, pages = {503--506}, abstract = {OBJECTIVES: Our study aims to determine the age of onset of adult-type hypolactasia in Sardinians, and to establish the age at which genotyping of the C/T-13910 variant can be used reliably in the diagnosis of lactose malabsorption. PATIENTS AND METHODS: A lactose breath hydrogen test was given to 383 randomly selected patients, from 3 to 19 years old. RESULTS: The C/C-13910 genotype was found in 90% of patients; the frequency of the positive lactose breath hydrogen test increased with age and reached a prevalence of 85% at 9 years. CONCLUSIONS: In Sardinians, adult-type hypolactasia becomes phenotypically evident in all individuals older than 9 years, suggesting that this should be considered the minimum age at which the genetic test for lactase nonpersistence should be applied.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVES: Our study aims to determine the age of onset of adult-type hypolactasia in Sardinians, and to establish the age at which genotyping of the C/T-13910 variant can be used reliably in the diagnosis of lactose malabsorption. PATIENTS AND METHODS: A lactose breath hydrogen test was given to 383 randomly selected patients, from 3 to 19 years old. RESULTS: The C/C-13910 genotype was found in 90% of patients; the frequency of the positive lactose breath hydrogen test increased with age and reached a prevalence of 85% at 9 years. CONCLUSIONS: In Sardinians, adult-type hypolactasia becomes phenotypically evident in all individuals older than 9 years, suggesting that this should be considered the minimum age at which the genetic test for lactase nonpersistence should be applied. |
Schirru, E; Corona, V; Usai-Satta, P; Scarpa, M; Oppia, F; Loriga, F; Cucca, F; De Virgiliis, S; Rossino, R; Macis, Doloretta M; Jores, R -D; Congia, M Genetic testing improves the diagnosis of adult type hypolactasia in the Mediterranean population of Sardinia. Journal Article Eur J Clin Nutr, 61 (10), pp. 1220–1225, 2007, ISSN: 0954-3007 0954-3007. @article{schirru_genetic_2007, title = {Genetic testing improves the diagnosis of adult type hypolactasia in the Mediterranean population of Sardinia.}, author = {Schirru, E. and Corona, V. and Usai-Satta, P. and Scarpa, M. and Oppia, F. and Loriga, F. and Cucca, F. and De Virgiliis, S. and Rossino, R. and Macis, M. Doloretta and Jores, R.-D. and Congia, M.}, doi = {10.1038/sj.ejcn.1602638}, issn = {0954-3007 0954-3007}, year = {2007}, date = {2007-10-01}, journal = {Eur J Clin Nutr}, volume = {61}, number = {10}, pages = {1220--1225}, abstract = {OBJECTIVE: Recently, the C/T-13910 polymorphism on chromosome 2q21 in North-European populations has been found completely associated with lactase activity and its genetic typing proposed as first-stage screening test for adult hypolactasia. However, the C/T-13910 variant in some sub-Saharan African groups is not a predictor of lactase persistence. In this work, we wanted to verify if in the Mediterranean island of Sardinia, located in Southern Europe, the C/T-13910 polymorphism may be useful or not for the diagnosis of adult type hypolactasia. DESIGN: Validation study of a genetic testing for adult type hypolactasia in Sardinians. SETTING: Brotzu Hospital and Microcitemico Hospital, Cagliari, Italy. SUBJECTS: The sample consisted in 84 Sardinian individuals (63 women and 21 men; range 20-73 years) selected from a group of 832 patients. METHODS: Genetic testing was compared to an improved test obtained by a combination of different breath hydrogen tests and clinical assessment. RESULTS: We found that all 49 individuals with lactose malabsorption, demonstrated by a combination of different breath hydrogen tests and clinical assessment, carried the C/C-13910 genotype associated with lactase non-persistence, 23 individuals with lactose normal absorption carried the C/T-13910 genotype associated with lactase persistence and only one person with the above phenotype showed a discordant C/C-13910 genotype. The genetic testing showed very high sensitivity, specificity, positive and negative predictive values of 100, 95.8, 98 and 100%, respectively. CONCLUSIONS: Sardinians, unlike some ethnic groups in sub-Saharan Africa, show the same genetic association of hypolactasia with the C/T-13910 variant as other North-European populations. The genetic testing for the C/T-13910 variant may contribute to improving the diagnosis of adult type hypolactasia.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: Recently, the C/T-13910 polymorphism on chromosome 2q21 in North-European populations has been found completely associated with lactase activity and its genetic typing proposed as first-stage screening test for adult hypolactasia. However, the C/T-13910 variant in some sub-Saharan African groups is not a predictor of lactase persistence. In this work, we wanted to verify if in the Mediterranean island of Sardinia, located in Southern Europe, the C/T-13910 polymorphism may be useful or not for the diagnosis of adult type hypolactasia. DESIGN: Validation study of a genetic testing for adult type hypolactasia in Sardinians. SETTING: Brotzu Hospital and Microcitemico Hospital, Cagliari, Italy. SUBJECTS: The sample consisted in 84 Sardinian individuals (63 women and 21 men; range 20-73 years) selected from a group of 832 patients. METHODS: Genetic testing was compared to an improved test obtained by a combination of different breath hydrogen tests and clinical assessment. RESULTS: We found that all 49 individuals with lactose malabsorption, demonstrated by a combination of different breath hydrogen tests and clinical assessment, carried the C/C-13910 genotype associated with lactase non-persistence, 23 individuals with lactose normal absorption carried the C/T-13910 genotype associated with lactase persistence and only one person with the above phenotype showed a discordant C/C-13910 genotype. The genetic testing showed very high sensitivity, specificity, positive and negative predictive values of 100, 95.8, 98 and 100%, respectively. CONCLUSIONS: Sardinians, unlike some ethnic groups in sub-Saharan Africa, show the same genetic association of hypolactasia with the C/T-13910 variant as other North-European populations. The genetic testing for the C/T-13910 variant may contribute to improving the diagnosis of adult type hypolactasia. |
Thomson, G; Valdes, A M; Noble, J A; Kockum, I; Grote, M N; Najman, J; Erlich, H A; Cucca, F; Pugliese, A; Steenkiste, A; Dorman, J S; Caillat-Zucman, S; Hermann, R; Ilonen, J; Lambert, A P; Bingley, P J; Gillespie, K M; Lernmark, A; Sanjeevi, C B; Ronningen, K S; Undlien, D E; Thorsby, E; Petrone, A; Buzzetti, R; Koeleman, B P C; Roep, B O; Saruhan-Direskeneli, G; Uyar, F A; Gunoz, H; Gorodezky, C; Alaez, C; Boehm, B O; Mlynarski, W; Ikegami, H; Berrino, M; Fasano, M E; Dametto, E; Israel, S; Brautbar, C; Santiago-Cortes, A; Frazer de Llado, T; She, J -X; Bugawan, T L; Rotter, J I; Raffel, L; Zeidler, A; Leyva-Cobian, F; Hawkins, B R; Chan, S H; Castano, L; Pociot, F; Nerup, J Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Journal Article Tissue Antigens, 70 (2), pp. 110–127, 2007, ISSN: 0001-2815 0001-2815. @article{thomson_relative_2007, title = {Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis.}, author = {Thomson, G. and Valdes, A. M. and Noble, J. A. and Kockum, I. and Grote, M. N. and Najman, J. and Erlich, H. A. and Cucca, F. and Pugliese, A. and Steenkiste, A. and Dorman, J. S. and Caillat-Zucman, S. and Hermann, R. and Ilonen, J. and Lambert, A. P. and Bingley, P. J. and Gillespie, K. M. and Lernmark, A. and Sanjeevi, C. B. and Ronningen, K. S. and Undlien, D. E. and Thorsby, E. and Petrone, A. and Buzzetti, R. and Koeleman, B. P. C. and Roep, B. O. and Saruhan-Direskeneli, G. and Uyar, F. A. and Gunoz, H. and Gorodezky, C. and Alaez, C. and Boehm, B. O. and Mlynarski, W. and Ikegami, H. and Berrino, M. and Fasano, M. E. and Dametto, E. and Israel, S. and Brautbar, C. and Santiago-Cortes, A. and Frazer de Llado, T. and She, J.-X. and Bugawan, T. L. and Rotter, J. I. and Raffel, L. and Zeidler, A. and Leyva-Cobian, F. and Hawkins, B. R. and Chan, S. H. and Castano, L. and Pociot, F. and Nerup, J.}, doi = {10.1111/j.1399-0039.2007.00867.x}, issn = {0001-2815 0001-2815}, year = {2007}, date = {2007-08-01}, journal = {Tissue Antigens}, volume = {70}, number = {2}, pages = {110--127}, abstract = {The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 textgreater *0404 textgreater *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 textgreater *0404 textgreater *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels. |
Sellaroli, Valentina ; Cucca, Francesco ; Santosuosso, Amedeo Shared genetic data and the rights of involved people. Journal Article Rev Derecho Genoma Hum, (26), pp. 193–231, 2007, ISSN: 1134-7198 1134-7198. @article{sellaroli_shared_2007, title = {Shared genetic data and the rights of involved people.}, author = {Sellaroli, Valentina and Cucca, Francesco and Santosuosso, Amedeo}, issn = {1134-7198 1134-7198}, year = {2007}, date = {2007-06-01}, journal = {Rev Derecho Genoma Hum}, number = {26}, pages = {193--231}, abstract = {The authors examine the two main attitudes toward genetics: Exceptionalism and Undervaluation. They firstly pose the basis of the matter from the scientific point of view and then verify how these two attitudes really work in the different fields where human genetics finds relevant applications, dealing with the questions arising from the unique characteristics of genetic data that is shared among the whole bio-group. Then some judicial cases related to the conflicts arising when genetic data are stored in repositories, whatever the aims and reasons, are presented and discussed. The matter is then considered from the criminal law perspective, in the light of the new possible implications of DNA fingerprinting in criminal investigations. Finally, some general considerations on opposing Exceptionalism/Undervaluation viewpoints and the real reason for making up new rules are presented.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The authors examine the two main attitudes toward genetics: Exceptionalism and Undervaluation. They firstly pose the basis of the matter from the scientific point of view and then verify how these two attitudes really work in the different fields where human genetics finds relevant applications, dealing with the questions arising from the unique characteristics of genetic data that is shared among the whole bio-group. Then some judicial cases related to the conflicts arising when genetic data are stored in repositories, whatever the aims and reasons, are presented and discussed. The matter is then considered from the criminal law perspective, in the light of the new possible implications of DNA fingerprinting in criminal investigations. Finally, some general considerations on opposing Exceptionalism/Undervaluation viewpoints and the real reason for making up new rules are presented. |
Bonfigli, Silvana ; Fozza, Claudio ; Contini, Salvatore ; Buzzetti, Raffaella ; Cucca, Francesco ; Longinotti, Maurizio High frequency of the TCRBV20S1 null allele in the Sardinian population. Journal Article Hum Immunol, 68 (5), pp. 426–429, 2007, ISSN: 0198-8859 0198-8859. @article{bonfigli_high_2007, title = {High frequency of the TCRBV20S1 null allele in the Sardinian population.}, author = {Bonfigli, Silvana and Fozza, Claudio and Contini, Salvatore and Buzzetti, Raffaella and Cucca, Francesco and Longinotti, Maurizio}, doi = {10.1016/j.humimm.2007.01.011}, issn = {0198-8859 0198-8859}, year = {2007}, date = {2007-05-01}, journal = {Hum Immunol}, volume = {68}, number = {5}, pages = {426--429}, abstract = {Single nucleotide polymorphisms (SNPs) in the T-cell receptor (TCR) gene segments might play a role in shaping the TCR repertoire. Three polymorphisms have been described for the TCRBV20S1 gene segment, one of which is responsible for a nucleotide substitution at position 524, resulting in the introduction of a stop codon. Individuals homozygous for this inactivating polymorphism ("null allele") are unable to express TCRBV20 gene products. Using DNA restriction digestion analysis, we investigated the frequency of this polymorphism in 111 healthy Sardinian subjects. Inhabitants of the Mediterranean island of Sardinia are considered to represent a genetically isolated population. Our analyses revealed an incidence of 19.8% of homozygosity for the null allele, corresponding to an allele frequency of 0.45. Such an incidence, significantly higher than the one detected in 83 non-Sardinian Caucasians (6%), is the most elevated so far reported in the literature. BV20 is a single member subfamily and the null allele produces a gap in the potential TCR repertoire. Therefore, it is possible that an undetermined selective pressure could have played a role in determining the high frequency of this inactivating polymorphism in Sardinians. Alternatively, this finding could be related to a founder effect in this ancient island population.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Single nucleotide polymorphisms (SNPs) in the T-cell receptor (TCR) gene segments might play a role in shaping the TCR repertoire. Three polymorphisms have been described for the TCRBV20S1 gene segment, one of which is responsible for a nucleotide substitution at position 524, resulting in the introduction of a stop codon. Individuals homozygous for this inactivating polymorphism ("null allele") are unable to express TCRBV20 gene products. Using DNA restriction digestion analysis, we investigated the frequency of this polymorphism in 111 healthy Sardinian subjects. Inhabitants of the Mediterranean island of Sardinia are considered to represent a genetically isolated population. Our analyses revealed an incidence of 19.8% of homozygosity for the null allele, corresponding to an allele frequency of 0.45. Such an incidence, significantly higher than the one detected in 83 non-Sardinian Caucasians (6%), is the most elevated so far reported in the literature. BV20 is a single member subfamily and the null allele produces a gap in the potential TCR repertoire. Therefore, it is possible that an undetermined selective pressure could have played a role in determining the high frequency of this inactivating polymorphism in Sardinians. Alternatively, this finding could be related to a founder effect in this ancient island population. |
Marrosu, Maria Giovanna ; Murru, Raffaele ; Costa, Gianna ; Melis, Maria Cristina ; Rolesu, Marcella ; Schirru, Lucia ; Solla, Elisabetta ; Cuccu, Stefania ; Secci, Maria Antonietta ; Whalen, Michael B; Cocco, Eleonora ; Pugliatti, Maura ; Sotgiu, Stefano ; Rosati, Giulio ; Cucca, Francesco Variation of the myelin oligodendrocyte glycoprotein gene is not primarily associated with multiple sclerosis in the Sardinian population. Journal Article BMC Genet, 8 , pp. 25, 2007, ISSN: 1471-2156 1471-2156. @article{marrosu_variation_2007, title = {Variation of the myelin oligodendrocyte glycoprotein gene is not primarily associated with multiple sclerosis in the Sardinian population.}, author = {Marrosu, Maria Giovanna and Murru, Raffaele and Costa, Gianna and Melis, Maria Cristina and Rolesu, Marcella and Schirru, Lucia and Solla, Elisabetta and Cuccu, Stefania and Secci, Maria Antonietta and Whalen, Michael B. and Cocco, Eleonora and Pugliatti, Maura and Sotgiu, Stefano and Rosati, Giulio and Cucca, Francesco}, doi = {10.1186/1471-2156-8-25}, issn = {1471-2156 1471-2156}, year = {2007}, date = {2007-05-01}, journal = {BMC Genet}, volume = {8}, pages = {25}, abstract = {BACKGROUND: Multiple sclerosis (MS) is consistently associated with particular}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Multiple sclerosis (MS) is consistently associated with particular |
Jores, Rita-Desiree ; Frau, Fulvia ; Cucca, Francesco ; Grazia Clemente, Maria ; Orru, Sandra ; Rais, Marco ; De Virgiliis, Stefano ; Congia, Mauro HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease. Journal Article Scand J Gastroenterol, 42 (1), pp. 48–53, 2007, ISSN: 0036-5521 0036-5521. @article{jores_hla-dqb1*0201_2007, title = {HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease.}, author = {Jores, Rita-Desiree and Frau, Fulvia and Cucca, Francesco and Grazia Clemente, Maria and Orru, Sandra and Rais, Marco and De Virgiliis, Stefano and Congia, Mauro}, doi = {10.1080/00365520600789859}, issn = {0036-5521 0036-5521}, year = {2007}, date = {2007-01-01}, journal = {Scand J Gastroenterol}, volume = {42}, number = {1}, pages = {48--53}, abstract = {OBJECTIVE: Celiac disease (CD) is a T-lymphocyte-mediated small intestinal enteropathy triggered and maintained by dietary gluten, with a strong genetic component mapping to the HLA genes encoding for the class II DQ(alpha1*0501, beta1*02) molecule. Damage of the small intestine may cause a variety of clinical signs ranging from isolated long-standing iron-deficiency anemia refractory to iron supplementation to forms of severe malnutrition that may become life threatening. However, patients carrying the typical intestinal lesions of CD and presenting no symptoms at all (silent CD) are also a common clinical observation. Since it is commonly assumed that clinical signs and symptoms tend to correlate with the severity of the intestinal damage, the purpose of this study was to investigate whether particular HLA class II genotypes might also influence the extent of intestinal damage and consequently the clinical presentation of the disease. MATERIAL AND METHODS: We retrospectively compared histological grading of celiac disease intestinal biopsies with HLA haplotype, age at onset of disease and clinical signs and symptoms. RESULTS: Our findings showed that homozygosis for the DQB1*0201 allele is associated with a higher severity of the histological score (ptextless0.008). Of note for the clinician, this work also suggests that the same type 3c of intestinal damage causes a different clinical syndrome, depending on the patient's age. CONCLUSIONS: The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: Celiac disease (CD) is a T-lymphocyte-mediated small intestinal enteropathy triggered and maintained by dietary gluten, with a strong genetic component mapping to the HLA genes encoding for the class II DQ(alpha1*0501, beta1*02) molecule. Damage of the small intestine may cause a variety of clinical signs ranging from isolated long-standing iron-deficiency anemia refractory to iron supplementation to forms of severe malnutrition that may become life threatening. However, patients carrying the typical intestinal lesions of CD and presenting no symptoms at all (silent CD) are also a common clinical observation. Since it is commonly assumed that clinical signs and symptoms tend to correlate with the severity of the intestinal damage, the purpose of this study was to investigate whether particular HLA class II genotypes might also influence the extent of intestinal damage and consequently the clinical presentation of the disease. MATERIAL AND METHODS: We retrospectively compared histological grading of celiac disease intestinal biopsies with HLA haplotype, age at onset of disease and clinical signs and symptoms. RESULTS: Our findings showed that homozygosis for the DQB1*0201 allele is associated with a higher severity of the histological score (ptextless0.008). Of note for the clinician, this work also suggests that the same type 3c of intestinal damage causes a different clinical syndrome, depending on the patient's age. CONCLUSIONS: The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease. |
2006 |
Orofino, Maria Grazia ; Contu, Daniela ; Argiolu, Francesca ; Sanna, Maria Adele ; Gaziev, Javid ; La Nasa, Giorgio ; Vacca, Adriana ; Cao, Antonio ; Cucca, Francesco No influence of chromosome Y haplogroup variation in acute graft-versus-host disease in sardinia. Journal Article Transplantation, 82 (11), pp. 1529–1532, 2006, ISSN: 0041-1337 0041-1337. @article{orofino_no_2006, title = {No influence of chromosome Y haplogroup variation in acute graft-versus-host disease in sardinia.}, author = {Orofino, Maria Grazia and Contu, Daniela and Argiolu, Francesca and Sanna, Maria Adele and Gaziev, Javid and La Nasa, Giorgio and Vacca, Adriana and Cao, Antonio and Cucca, Francesco}, doi = {10.1097/01.tp.0000235822.46197.61}, issn = {0041-1337 0041-1337}, year = {2006}, date = {2006-12-01}, journal = {Transplantation}, volume = {82}, number = {11}, pages = {1529--1532}, abstract = {The donor-recipient sex-related mismatch has been reported as a risk factor for acute graft-versus-host disease (GVHD). However, the results obtained in previous studies appear to be contradictory. Here we evaluate the impact of donor-recipient sex-related mismatch in a series of 204 Sardinian individuals (92.1% of them affected by Beta- Thalassemia major) who underwent bone marrow transplantation (BMT) from human leukocyte antigen (HLA) identical siblings. In all, 78 of these patients had acute GVHD (aGVHD). We found that also in this homogenous group of patients from a homogenous population, the donor-female/recipient-male pair provided an increased risk for aGVHD when compared with a reference donor-male/recipient-male pair (POR=2.3}, keywords = {}, pubstate = {published}, tppubtype = {article} } The donor-recipient sex-related mismatch has been reported as a risk factor for acute graft-versus-host disease (GVHD). However, the results obtained in previous studies appear to be contradictory. Here we evaluate the impact of donor-recipient sex-related mismatch in a series of 204 Sardinian individuals (92.1% of them affected by Beta- Thalassemia major) who underwent bone marrow transplantation (BMT) from human leukocyte antigen (HLA) identical siblings. In all, 78 of these patients had acute GVHD (aGVHD). We found that also in this homogenous group of patients from a homogenous population, the donor-female/recipient-male pair provided an increased risk for aGVHD when compared with a reference donor-male/recipient-male pair (POR=2.3 |
Bottini, Nunzio ; Vang, Torkel ; Cucca, Francesco ; Mustelin, Tomas Role of PTPN22 in type 1 diabetes and other autoimmune diseases Journal Article Seminars in Immunology, 18 (4), pp. 207–213, 2006, ISSN: 10445323. @article{Bottini2006, title = {Role of PTPN22 in type 1 diabetes and other autoimmune diseases}, author = {Bottini, Nunzio and Vang, Torkel and Cucca, Francesco and Mustelin, Tomas}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16697661 http://linkinghub.elsevier.com/retrieve/pii/S1044532306000455}, doi = {10.1016/j.smim.2006.03.008}, issn = {10445323}, year = {2006}, date = {2006-08-01}, journal = {Seminars in Immunology}, volume = {18}, number = {4}, pages = {207--213}, abstract = {We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease. |
Sapone, Anna ; de Magistris, Laura ; Pietzak, Michelle ; Clemente, Maria G; Tripathi, Amit ; Cucca, Francesco ; Lampis, Rosanna ; Kryszak, Deborah ; Carteni, Maria ; Generoso, Maddalena ; Iafusco, Dario ; Prisco, Francesco ; Laghi, Francesca ; Riegler, Gabriele ; Carratu, Romano ; Counts, Debra ; Fasano, Alessio Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Journal Article Diabetes, 55 (5), pp. 1443–1449, 2006, ISSN: 0012-1797 0012-1797. @article{sapone_zonulin_2006, title = {Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.}, author = {Sapone, Anna and de Magistris, Laura and Pietzak, Michelle and Clemente, Maria G. and Tripathi, Amit and Cucca, Francesco and Lampis, Rosanna and Kryszak, Deborah and Carteni, Maria and Generoso, Maddalena and Iafusco, Dario and Prisco, Francesco and Laghi, Francesca and Riegler, Gabriele and Carratu, Romano and Counts, Debra and Fasano, Alessio}, issn = {0012-1797 0012-1797}, year = {2006}, date = {2006-05-01}, journal = {Diabetes}, volume = {55}, number = {5}, pages = {1443--1449}, abstract = {Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals. |
2005 |
Vang, Torkel ; Congia, Mauro ; Macis, Maria Doloretta ; Musumeci, Lucia ; Orr{ú}, Valeria ; Zavattari, Patrizia ; Nika, Konstantina ; Tautz, Lutz ; Task{é}n, Kjetil ; Cucca, Francesco ; Mustelin, Tomas ; Bottini, Nunzio Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Journal Article Nature genetics, 37 (12), pp. 1317–9, 2005, ISSN: 1061-4036. @article{Vang2005, title = {Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant.}, author = {Vang, Torkel and Congia, Mauro and Macis, Maria Doloretta and Musumeci, Lucia and Orr{ú}, Valeria and Zavattari, Patrizia and Nika, Konstantina and Tautz, Lutz and Task{é}n, Kjetil and Cucca, Francesco and Mustelin, Tomas and Bottini, Nunzio}, url = {http://www.nature.com/doifinder/10.1038/ng1673 http://www.ncbi.nlm.nih.gov/pubmed/16273109}, doi = {10.1038/ng1673}, issn = {1061-4036}, year = {2005}, date = {2005-12-01}, journal = {Nature genetics}, volume = {37}, number = {12}, pages = {1317--9}, abstract = {A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant. |
Vang, Torkel ; Congia, Mauro ; Macis, Maria Doloretta ; Musumeci, Lucia ; Orru, Valeria ; Zavattari, Patrizia ; Nika, Konstantina ; Tautz, Lutz ; Tasken, Kjetil ; Cucca, Francesco ; Mustelin, Tomas ; Bottini, Nunzio Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Journal Article Nat Genet, 37 (12), pp. 1317–1319, 2005, ISSN: 1061-4036 1061-4036. @article{vang_autoimmune-associated_2005, title = {Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant.}, author = {Vang, Torkel and Congia, Mauro and Macis, Maria Doloretta and Musumeci, Lucia and Orru, Valeria and Zavattari, Patrizia and Nika, Konstantina and Tautz, Lutz and Tasken, Kjetil and Cucca, Francesco and Mustelin, Tomas and Bottini, Nunzio}, doi = {10.1038/ng1673}, issn = {1061-4036 1061-4036}, year = {2005}, date = {2005-12-01}, journal = {Nat Genet}, volume = {37}, number = {12}, pages = {1317--1319}, abstract = {A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant. |
2004 |
Motzo, Costantino ; Contu, Daniela ; Cordell, Heather J; Lampis, Rosanna ; Congia, Mauro ; Marrosu, Maria Giovanna ; Todd, John A; Devoto, Marcella ; Cucca, Francesco Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. Journal Article Diabetes, 53 (12), pp. 3286–3291, 2004, ISSN: 0012-1797 0012-1797. @article{motzo_heterogeneity_2004, title = {Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes.}, author = {Motzo, Costantino and Contu, Daniela and Cordell, Heather J. and Lampis, Rosanna and Congia, Mauro and Marrosu, Maria Giovanna and Todd, John A. and Devoto, Marcella and Cucca, Francesco}, issn = {0012-1797 0012-1797}, year = {2004}, date = {2004-12-01}, journal = {Diabetes}, volume = {53}, number = {12}, pages = {3286--3291}, abstract = {There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity. |
Marrosu, Maria Giovanna ; Motzo, Costantino ; Murru, Raffaele ; Lampis, Rosanna ; Costa, Gianna ; Zavattari, Patrizia ; Contu, Daniela ; Fadda, Elisabetta ; Cocco, Eleonora ; Cucca, Francesco The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone. Journal Article Human molecular genetics, 13 (23), pp. 2919–24, 2004, ISSN: 0964-6906. @article{Marrosu2004, title = {The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone.}, author = {Marrosu, Maria Giovanna and Motzo, Costantino and Murru, Raffaele and Lampis, Rosanna and Costa, Gianna and Zavattari, Patrizia and Contu, Daniela and Fadda, Elisabetta and Cocco, Eleonora and Cucca, Francesco}, url = {https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddh319 http://www.ncbi.nlm.nih.gov/pubmed/15471889}, doi = {10.1093/hmg/ddh319}, issn = {0964-6906}, year = {2004}, date = {2004-12-01}, journal = {Human molecular genetics}, volume = {13}, number = {23}, pages = {2919--24}, abstract = {Type 1 diabetes (T1D) and multiple sclerosis (MS) are two autoimmune diseases which exhibit a considerably higher incidence in Sardinia compared with the surrounding southern European populations. Surprisingly, a 5-fold increased prevalence of T1D has also been observed in Sardinian MS patients. Susceptibility to both disorders is associated with common variants of the HLA-DRB1 and -DQB1 loci. In this study, we determined the relative contribution of genotype variation of these loci to the co-occurrence of the two disorders in Sardinia. We genotyped 1052 T1D patients and 1049 MS patients (31 of whom also had T1D) together with 1917 ethnically matched controls. On the basis of the absolute risks for T1D of the HLA-DRB1-DQB1 genotypes, we established that these loci would only contribute to a 2-fold increase in T1D prevalence in MS patients. From this evidence, we conclude that shared disease associations due to the HLA-DRB1-DQB1 loci provide only a partial explanation for the observed increased prevalence of T1D in Sardinian MS patients. The data suggest that variation at other non-HLA class II loci, and/or unknown environmental factors contribute significantly to the co-occurrence of these two traits.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Type 1 diabetes (T1D) and multiple sclerosis (MS) are two autoimmune diseases which exhibit a considerably higher incidence in Sardinia compared with the surrounding southern European populations. Surprisingly, a 5-fold increased prevalence of T1D has also been observed in Sardinian MS patients. Susceptibility to both disorders is associated with common variants of the HLA-DRB1 and -DQB1 loci. In this study, we determined the relative contribution of genotype variation of these loci to the co-occurrence of the two disorders in Sardinia. We genotyped 1052 T1D patients and 1049 MS patients (31 of whom also had T1D) together with 1917 ethnically matched controls. On the basis of the absolute risks for T1D of the HLA-DRB1-DQB1 genotypes, we established that these loci would only contribute to a 2-fold increase in T1D prevalence in MS patients. From this evidence, we conclude that shared disease associations due to the HLA-DRB1-DQB1 loci provide only a partial explanation for the observed increased prevalence of T1D in Sardinian MS patients. The data suggest that variation at other non-HLA class II loci, and/or unknown environmental factors contribute significantly to the co-occurrence of these two traits. |
Koeleman, B P C; Lie, B A; Undlien, D E; Dudbridge, F; Thorsby, E; de Vries, R R P; Cucca, F; Roep, B O; Giphart, M J; Todd, J A Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Journal Article Genes Immun, 5 (5), pp. 381–388, 2004, ISSN: 1466-4879 1466-4879. @article{koeleman_genotype_2004, title = {Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease.}, author = {Koeleman, B. P. C. and Lie, B. A. and Undlien, D. E. and Dudbridge, F. and Thorsby, E. and de Vries, R. R. P. and Cucca, F. and Roep, B. O. and Giphart, M. J. and Todd, J. A.}, doi = {10.1038/sj.gene.6364106}, issn = {1466-4879 1466-4879}, year = {2004}, date = {2004-08-01}, journal = {Genes Immun}, volume = {5}, number = {5}, pages = {381--388}, abstract = {Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha 1, beta 1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of}, keywords = {}, pubstate = {published}, tppubtype = {article} } Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha 1, beta 1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of |
Zavattari, Patrizia ; Deidda, Elisabetta ; Pitzalis, Maristella ; Zoa, Barbara ; Moi, Loredana ; Lampis, Rosanna ; Contu, Daniela ; Motzo, Costantino ; Frongia, Paola ; Angius, Efisio ; Maioli, Mario ; Todd, John A; Cucca, Francesco No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population. Journal Article Diabetes, 53 (7), pp. 1911–1914, 2004, ISSN: 0012-1797 0012-1797. @article{zavattari_no_2004, title = {No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population.}, author = {Zavattari, Patrizia and Deidda, Elisabetta and Pitzalis, Maristella and Zoa, Barbara and Moi, Loredana and Lampis, Rosanna and Contu, Daniela and Motzo, Costantino and Frongia, Paola and Angius, Efisio and Maioli, Mario and Todd, John A. and Cucca, Francesco}, issn = {0012-1797 0012-1797}, year = {2004}, date = {2004-07-01}, journal = {Diabetes}, volume = {53}, number = {7}, pages = {1911--1914}, abstract = {Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and}, keywords = {}, pubstate = {published}, tppubtype = {article} } Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and |
2003 |
Maier, L M; Twells, R C J; Howson, J M M; Lam, A C; Clayton, D G; Smyth, D J; Savage, D; Carson, D; Patterson, C C; Smink, L J; Walker, N M; Burren, O S; Nutland, S; Rance, H; Tuomilehto-Wolf, E; Tuomilehto, J; Guja, C; Ionescu-Tirgoviste, C; Undlien, D E; Ronningen, K S; Cucca, F; Todd, J A Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene. Journal Article Genes Immun, 4 (7), pp. 469–475, 2003, ISSN: 1466-4879 1466-4879. @article{maier_testing_2003, title = {Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene.}, author = {Maier, L. M. and Twells, R. C. J. and Howson, J. M. M. and Lam, A. C. and Clayton, D. G. and Smyth, D. J. and Savage, D. and Carson, D. and Patterson, C. C. and Smink, L. J. and Walker, N. M. and Burren, O. S. and Nutland, S. and Rance, H. and Tuomilehto-Wolf, E. and Tuomilehto, J. and Guja, C. and Ionescu-Tirgoviste, C. and Undlien, D. E. and Ronningen, K. S. and Cucca, F. and Todd, J. A.}, doi = {10.1038/sj.gene.6364007}, issn = {1466-4879 1466-4879}, year = {2003}, date = {2003-10-01}, journal = {Genes Immun}, volume = {4}, number = {7}, pages = {469--475}, abstract = {Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 CtextgreaterT SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 CtextgreaterT SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 CtextgreaterT and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 CtextgreaterT SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 CtextgreaterT SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 CtextgreaterT and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one. |
Cucca, F; Contu, D; Zavattari, P; Murru, D [Correlation between major histocompatibility complex (MHC)-class II and type 1 diabetes]. Journal Article Minerva Endocrinol, 28 (2), pp. 111–122, 2003, ISSN: 0391-1977 0391-1977. @article{cucca_[correlation_2003, title = {[Correlation between major histocompatibility complex (MHC)-class II and type 1 diabetes].}, author = {Cucca, F. and Contu, D. and Zavattari, P. and Murru, D.}, issn = {0391-1977 0391-1977}, year = {2003}, date = {2003-06-01}, journal = {Minerva Endocrinol}, volume = {28}, number = {2}, pages = {111--122}, abstract = {The autoimmune disease type 1 diabetes (T1D) results from a T lymphocyte-dependent, selective destruction of the insulin-producing pancreatic beta-cells and subsequent irreversible insulin deficiency. The disease is caused by a combination of genetic and environmental factors. Numerous genetic, structural and biological studies have provided a convincing case that in human T1D and in its murine model, the non obese diabetes (NOD) mouse, the major histocompatibility complex (MHC) class II molecules, HLA-DQB1 and -DRB1 and their murine orthologues, IA and IE, are the major genetic determinants. The two loci act as a complex superlocus, with both haplotype- and genotype-specific effects. In humans the HLA class II molecule-association with the disease is constituted by a two-sided gradient from positively associated-high risk to negatively associated-low risk molecules. Very low risk corresponds to dominant protection from the disease. The protein structure of DQ/IA and DR/IE molecules have been established. Molecular modeling work revealed that there are marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules show conserved similarities that differ with the shared structural patterns observed between the protective molecules. The available data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall these observations suggest shared pathways in human and murine T1D.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The autoimmune disease type 1 diabetes (T1D) results from a T lymphocyte-dependent, selective destruction of the insulin-producing pancreatic beta-cells and subsequent irreversible insulin deficiency. The disease is caused by a combination of genetic and environmental factors. Numerous genetic, structural and biological studies have provided a convincing case that in human T1D and in its murine model, the non obese diabetes (NOD) mouse, the major histocompatibility complex (MHC) class II molecules, HLA-DQB1 and -DRB1 and their murine orthologues, IA and IE, are the major genetic determinants. The two loci act as a complex superlocus, with both haplotype- and genotype-specific effects. In humans the HLA class II molecule-association with the disease is constituted by a two-sided gradient from positively associated-high risk to negatively associated-low risk molecules. Very low risk corresponds to dominant protection from the disease. The protein structure of DQ/IA and DR/IE molecules have been established. Molecular modeling work revealed that there are marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules show conserved similarities that differ with the shared structural patterns observed between the protective molecules. The available data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall these observations suggest shared pathways in human and murine T1D. |
Ueda, Hironori ; Howson, Joanna M M; Esposito, Laura ; Heward, Joanne ; Snook, Hywel ; Chamberlain, Giselle ; Rainbow, Daniel B; Hunter, Kara M D; Smith, Annabel N; Di Genova, Gianfranco ; Herr, Mathias H; Dahlman, Ingrid ; Payne, Felicity ; Smyth, Deborah ; Lowe, Christopher ; Twells, Rebecca C J; Howlett, Sarah ; Healy, Barry ; Nutland, Sarah ; Rance, Helen E; Everett, Vin ; Smink, Luc J; Lam, Alex C; Cordell, Heather J; Walker, Neil M; Bordin, Cristina ; Hulme, John ; Motzo, Costantino ; Cucca, Francesco ; Hess, Fred J; Metzker, Michael L; Rogers, Jane ; Gregory, Simon ; Allahabadia, Amit ; Nithiyananthan, Ratnasingam ; Tuomilehto-Wolf, Eva ; Tuomilehto, Jaakko ; Bingley, Polly ; Gillespie, Kathleen M; Undlien, Dag E; Ronningen, Kjersti S; Guja, Cristian ; Ionescu-Tirgoviste, Constantin ; Savage, David A; Maxwell, Peter A; Carson, Dennis J; Patterson, Chris C; Franklyn, Jayne A; Clayton, David G; Peterson, Laurence B; Wicker, Linda S; Todd, John A; Gough, Stephen C L Association of the Ŧ-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Journal Article Nature, 423 (6939), pp. 506–511, 2003, ISSN: 0028-0836 0028-0836. @article{ueda_association_2003, title = {Association of the Ŧ-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.}, author = {Ueda, Hironori and Howson, Joanna M. M. and Esposito, Laura and Heward, Joanne and Snook, Hywel and Chamberlain, Giselle and Rainbow, Daniel B. and Hunter, Kara M. D. and Smith, Annabel N. and Di Genova, Gianfranco and Herr, Mathias H. and Dahlman, Ingrid and Payne, Felicity and Smyth, Deborah and Lowe, Christopher and Twells, Rebecca C. J. and Howlett, Sarah and Healy, Barry and Nutland, Sarah and Rance, Helen E. and Everett, Vin and Smink, Luc J. and Lam, Alex C. and Cordell, Heather J. and Walker, Neil M. and Bordin, Cristina and Hulme, John and Motzo, Costantino and Cucca, Francesco and Hess, J. Fred and Metzker, Michael L. and Rogers, Jane and Gregory, Simon and Allahabadia, Amit and Nithiyananthan, Ratnasingam and Tuomilehto-Wolf, Eva and Tuomilehto, Jaakko and Bingley, Polly and Gillespie, Kathleen M. and Undlien, Dag E. and Ronningen, Kjersti S. and Guja, Cristian and Ionescu-Tirgoviste, Constantin and Savage, David A. and Maxwell, A. Peter and Carson, Dennis J. and Patterson, Chris C. and Franklyn, Jayne A. and Clayton, David G. and Peterson, Laurence B. and Wicker, Linda S. and Todd, John A. and Gough, Stephen C. L.}, doi = {10.1038/nature01621}, issn = {0028-0836 0028-0836}, year = {2003}, date = {2003-05-01}, journal = {Nature}, volume = {423}, number = {6939}, pages = {506--511}, abstract = {Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction. |
2002 |
Contu, Daniela ; Morelli, Laura ; Zavattari, Patrizia ; Lampis, Rosanna ; Angius, Efisio ; Frongia, Paola ; Murru, Daniela ; Maioli, Mario ; Francalacci, Paolo ; Todd, John A; Cucca, Francesco Sex-related bias and exclusion mapping of the nonrecombinant portion of chromosome Y in human type 1 diabetes in the isolated founder population of Sardinia. Journal Article Diabetes, 51 (12), pp. 3573–3576, 2002, ISSN: 0012-1797 0012-1797. @article{contu_sex-related_2002, title = {Sex-related bias and exclusion mapping of the nonrecombinant portion of chromosome Y in human type 1 diabetes in the isolated founder population of Sardinia.}, author = {Contu, Daniela and Morelli, Laura and Zavattari, Patrizia and Lampis, Rosanna and Angius, Efisio and Frongia, Paola and Murru, Daniela and Maioli, Mario and Francalacci, Paolo and Todd, John A. and Cucca, Francesco}, issn = {0012-1797 0012-1797}, year = {2002}, date = {2002-12-01}, journal = {Diabetes}, volume = {51}, number = {12}, pages = {3573--3576}, abstract = {A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male- to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3}, keywords = {}, pubstate = {published}, tppubtype = {article} } A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male- to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3 |
Dahlman, Ingrid ; Eaves, Iain A; Kosoy, Roman ; Morrison, Anne V; Heward, Joanne ; Gough, Stephen C L; Allahabadia, Amit ; Franklyn, Jayne A; Tuomilehto, Jaakko ; Tuomilehto-Wolf, Eva ; Cucca, Francesco ; Guja, Cristian ; Ionescu-Tirgoviste, Constantin ; Stevens, Helen ; Carr, Philippa ; Nutland, Sarah ; McKinney, Patricia ; Shield, Julian P; Wang, William ; Cordell, Heather J; Walker, Neil ; Todd, John A; Concannon, Patrick Parameters for reliable results in genetic association studies in common disease. Journal Article Nat Genet, 30 (2), pp. 149–150, 2002, ISSN: 1061-4036 1061-4036. @article{dahlman_parameters_2002, title = {Parameters for reliable results in genetic association studies in common disease.}, author = {Dahlman, Ingrid and Eaves, Iain A. and Kosoy, Roman and Morrison, V. Anne and Heward, Joanne and Gough, Stephen C. L. and Allahabadia, Amit and Franklyn, Jayne A. and Tuomilehto, Jaakko and Tuomilehto-Wolf, Eva and Cucca, Francesco and Guja, Cristian and Ionescu-Tirgoviste, Constantin and Stevens, Helen and Carr, Philippa and Nutland, Sarah and McKinney, Patricia and Shield, Julian P. and Wang, William and Cordell, Heather J. and Walker, Neil and Todd, John A. and Concannon, Patrick}, doi = {10.1038/ng825}, issn = {1061-4036 1061-4036}, year = {2002}, date = {2002-02-01}, journal = {Nat Genet}, volume = {30}, number = {2}, pages = {149--150}, abstract = {It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.}, keywords = {}, pubstate = {published}, tppubtype = {article} } It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable. |
2001 |
Marrosu, M G; Murru, R; Murru, M R; Costa, G; Zavattari, P; Whalen, M; Cocco, E; Mancosu, C; Schirru, L; Solla, E; Fadda, E; Melis, C; Porru, I; Rolesu, M; Cucca, F Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Journal Article Human molecular genetics, 10 (25), pp. 2907–16, 2001, ISSN: 0964-6906. @article{Marrosu2001, title = {Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.}, author = {Marrosu, M G and Murru, R and Murru, M R and Costa, G and Zavattari, P and Whalen, M and Cocco, E and Mancosu, C and Schirru, L and Solla, E and Fadda, E and Melis, C and Porru, I and Rolesu, M and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11741834}, issn = {0964-6906}, year = {2001}, date = {2001-12-01}, journal = {Human molecular genetics}, volume = {10}, number = {25}, pages = {2907--16}, abstract = {Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS. |
Catassi, C; Doloretta Macis, M; Ratsch, I M; De Virgiliis, S; Cucca, F The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence. Journal Article Tissue Antigens, 58 (6), pp. 402–406, 2001, ISSN: 0001-2815 0001-2815. @article{catassi_distribution_2001, title = {The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence.}, author = {Catassi, C. and Doloretta Macis, M. and Ratsch, I. M. and De Virgiliis, S. and Cucca, F.}, issn = {0001-2815 0001-2815}, year = {2001}, date = {2001-12-01}, journal = {Tissue Antigens}, volume = {58}, number = {6}, pages = {402--406}, abstract = {Celiac disease (CD) is a multifactorial disorder of the small intestine caused by a permanent dietary intolerance to gluten. The combined presence of the HLA class II DQA1*0501 and DQB1*0201 alleles represents the major genetic component for disease predisposition. It has been shown that the Saharawi refugees living in northern Africa have a very high frequency of CD. In the present study we analysed this population to evaluate the degree of association with CD of the haplotypes and genotypes at the main HLA-DQB1 and DQA1 disease loci. We found a strong association of the DR3, DQB1*0201-DQA1*0501-positive haplotypes and genotypes. A very high frequency of DR3, DQB1*0201-DQA1*0501 was also observed in the general Saharawi population. These results indicate that there is a good correlation between disease prevalence and frequency of the main predisposing haplotype in the background population. However, the correlation is incomplete because similar frequencies of DR3 are also observed in populations such as the Sardinians showing a much lower prevalence of CD. We can conclude that the distribution of DQ genes in the Saharawi population only provides a partial explanation for the high prevalence of CD. Other factors, such as rapidly changing dietary habits and/or non-DQ genes, may also play some role.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Celiac disease (CD) is a multifactorial disorder of the small intestine caused by a permanent dietary intolerance to gluten. The combined presence of the HLA class II DQA1*0501 and DQB1*0201 alleles represents the major genetic component for disease predisposition. It has been shown that the Saharawi refugees living in northern Africa have a very high frequency of CD. In the present study we analysed this population to evaluate the degree of association with CD of the haplotypes and genotypes at the main HLA-DQB1 and DQA1 disease loci. We found a strong association of the DR3, DQB1*0201-DQA1*0501-positive haplotypes and genotypes. A very high frequency of DR3, DQB1*0201-DQA1*0501 was also observed in the general Saharawi population. These results indicate that there is a good correlation between disease prevalence and frequency of the main predisposing haplotype in the background population. However, the correlation is incomplete because similar frequencies of DR3 are also observed in populations such as the Sardinians showing a much lower prevalence of CD. We can conclude that the distribution of DQ genes in the Saharawi population only provides a partial explanation for the high prevalence of CD. Other factors, such as rapidly changing dietary habits and/or non-DQ genes, may also play some role. |
Cucca, F; Lampis, R; Congia, M; Angius, E; Nutland, S; Bain, S C; Barnett, A H; Todd, J A A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Journal Article Human molecular genetics, 10 (19), pp. 2025–37, 2001, ISSN: 0964-6906. @article{Cucca2001a, title = {A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.}, author = {Cucca, F and Lampis, R and Congia, M and Angius, E and Nutland, S and Bain, S C and Barnett, A H and Todd, J A}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11590120}, issn = {0964-6906}, year = {2001}, date = {2001-09-01}, journal = {Human molecular genetics}, volume = {10}, number = {19}, pages = {2025--37}, abstract = {In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D. |
Pociot, F; Larsen, Z M; Zavattari, P; Deidda, E; Nerup, J; Cattaneo, M; Chiaramonte, R; Comi, P; Sabbadini, M; Zollo, M; Biunno, I; Cucca, F No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility. Journal Article Diabetes Metab Res Rev, 17 (4), pp. 292–295, 2001, ISSN: 1520-7552 1520-7552. @article{pociot_no_2001, title = {No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility.}, author = {Pociot, F. and Larsen, Z. M. and Zavattari, P. and Deidda, E. and Nerup, J. and Cattaneo, M. and Chiaramonte, R. and Comi, P. and Sabbadini, M. and Zollo, M. and Biunno, I. and Cucca, F.}, issn = {1520-7552 1520-7552}, year = {2001}, date = {2001-08-01}, journal = {Diabetes Metab Res Rev}, volume = {17}, number = {4}, pages = {292--295}, abstract = {BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish |
Cucca, F; Dudbridge, F; Loddo, M; Mulargia, A P; Lampis, R; Angius, E; {De Virgiliis}, S; Koeleman, B P; Bain, S C; Barnett, A H; Gilchrist, F; Cordell, H; Welsh, K; Todd, J A The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1. Journal Article Diabetes, 50 (5), pp. 1200–5, 2001, ISSN: 0012-1797. @article{Cucca2001, title = {The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1.}, author = {Cucca, F and Dudbridge, F and Loddo, M and Mulargia, A P and Lampis, R and Angius, E and {De Virgiliis}, S and Koeleman, B P and Bain, S C and Barnett, A H and Gilchrist, F and Cordell, H and Welsh, K and Todd, J A}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11334427}, issn = {0012-1797}, year = {2001}, date = {2001-05-01}, journal = {Diabetes}, volume = {50}, number = {5}, pages = {1200--5}, abstract = {The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1. |
Zavattari, P; Lampis, R; Motzo, C; Loddo, M; Mulargia, A; Whalen, M; Maioli, M; Angius, E; Todd, J A; Cucca, F Human molecular genetics, 10 (8), pp. 881–9, 2001, ISSN: 0964-6906. @article{Zavattari2001, title = {Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci.}, author = {Zavattari, P and Lampis, R and Motzo, C and Loddo, M and Mulargia, A and Whalen, M and Maioli, M and Angius, E and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11285254}, issn = {0964-6906}, year = {2001}, date = {2001-04-01}, journal = {Human molecular genetics}, volume = {10}, number = {8}, pages = {881--9}, abstract = {Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits. |
Cucca, F; Lampis, R; Congia, M; Angius, E; Nutland, S; Bain, S C; Barnett, A H; Todd, J A A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Journal Article Hum Mol Genet, 10 (19), pp. 2025–2037, 2001, ISSN: 0964-6906 0964-6906. @article{cucca_correlation_2001, title = {A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.}, author = {Cucca, F. and Lampis, R. and Congia, M. and Angius, E. and Nutland, S. and Bain, S. C. and Barnett, A. H. and Todd, J. A.}, issn = {0964-6906 0964-6906}, year = {2001}, date = {2001-01-01}, journal = {Hum Mol Genet}, volume = {10}, number = {19}, pages = {2025--2037}, abstract = {In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D. |
Merriman, T R; Cordell, H J; Eaves, I A; Danoy, P A; Coraddu, F; Barber, R; Cucca, F; Broadley, S; Sawcer, S; Compston, A; Wordsworth, P; Shatford, J; Laval, S; Jirholt, J; Holmdahl, R; Theofilopoulos, A N; Kono, D H; Tuomilehto, J; Tuomilehto-Wolf, E; Buzzetti, R; Marrosu, M G; Undlien, D E; Ronningen, K S; Ionesco-Tirgoviste, C; Shield, J P; Pociot, F; Nerup, J; Jacob, C O; Polychronakos, C; Bain, S C; Todd, J A Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases. Journal Article Diabetes, 50 (1), pp. 184–194, 2001, ISSN: 0012-1797 0012-1797. @article{merriman_suggestive_2001, title = {Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases.}, author = {Merriman, T. R. and Cordell, H. J. and Eaves, I. A. and Danoy, P. A. and Coraddu, F. and Barber, R. and Cucca, F. and Broadley, S. and Sawcer, S. and Compston, A. and Wordsworth, P. and Shatford, J. and Laval, S. and Jirholt, J. and Holmdahl, R. and Theofilopoulos, A. N. and Kono, D. H. and Tuomilehto, J. and Tuomilehto-Wolf, E. and Buzzetti, R. and Marrosu, M. G. and Undlien, D. E. and Ronningen, K. S. and Ionesco-Tirgoviste, C. and Shield, J. P. and Pociot, F. and Nerup, J. and Jacob, C. O. and Polychronakos, C. and Bain, S. C. and Todd, J. A.}, issn = {0012-1797 0012-1797}, year = {2001}, date = {2001-01-01}, journal = {Diabetes}, volume = {50}, number = {1}, pages = {184--194}, abstract = {Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species. |
2000 |
Zavattari, P; Lampis, R; Mulargia, A; Loddo, M; Angius, E; Todd, J A; Cucca, F Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia. Journal Article Human molecular genetics, 9 (20), pp. 2967–72, 2000, ISSN: 0964-6906. @article{Zavattari2000, title = {Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia.}, author = {Zavattari, P and Lampis, R and Mulargia, A and Loddo, M and Angius, E and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11115840}, issn = {0964-6906}, year = {2000}, date = {2000-12-01}, journal = {Human molecular genetics}, volume = {9}, number = {20}, pages = {2967--72}, abstract = {There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapped with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known to be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a validation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatellite markers, we determined the peak of LD to be located at marker D6S2447, which is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defining allelic variation at functional candidate genes within the critical region. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the class II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping.}, keywords = {}, pubstate = {published}, tppubtype = {article} } There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapped with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known to be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a validation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatellite markers, we determined the peak of LD to be located at marker D6S2447, which is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defining allelic variation at functional candidate genes within the critical region. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the class II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping. |
Zavattari, P; Deidda, E; Whalen, M; Lampis, R; Mulargia, A; Loddo, M; Eaves, I; Mastio, G; Todd, J A; Cucca, F Human molecular genetics, 9 (20), pp. 2947–57, 2000, ISSN: 0964-6906. @article{Zavattari2000a, title = {Major factors influencing linkage disequilibrium by analysis of different chromosome regions in distinct populations: demography, chromosome recombination frequency and selection.}, author = {Zavattari, P and Deidda, E and Whalen, M and Lampis, R and Mulargia, A and Loddo, M and Eaves, I and Mastio, G and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11115838}, issn = {0964-6906}, year = {2000}, date = {2000-12-01}, journal = {Human molecular genetics}, volume = {9}, number = {20}, pages = {2947--57}, abstract = {Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations. |
Lampis, R; Morelli, L; De Virgiliis, S; Congia, M; Cucca, F The distribution of HLA class II haplotypes reveals that the Sardinian population is genetically differentiated from the other Caucasian populations. Journal Article Tissue Antigens, 56 (6), pp. 515–521, 2000, ISSN: 0001-2815 0001-2815. @article{lampis_distribution_2000, title = {The distribution of HLA class II haplotypes reveals that the Sardinian population is genetically differentiated from the other Caucasian populations.}, author = {Lampis, R. and Morelli, L. and De Virgiliis, S. and Congia, M. and Cucca, F.}, issn = {0001-2815 0001-2815}, year = {2000}, date = {2000-12-01}, journal = {Tissue Antigens}, volume = {56}, number = {6}, pages = {515--521}, abstract = {In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both}, keywords = {}, pubstate = {published}, tppubtype = {article} } In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both |
Lampis, R; Morelli, L; Congia, M; Macis, M D; Mulargia, A; Loddo, M; {De Virgiliis}, S; Marrosu, M G; Todd, J A; Cucca, F Human molecular genetics, 9 (20), pp. 2959–65, 2000, ISSN: 0964-6906. @article{Lampis2000, title = {The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases.}, author = {Lampis, R and Morelli, L and Congia, M and Macis, M D and Mulargia, A and Loddo, M and {De Virgiliis}, S and Marrosu, M G and Todd, J A and Cucca, F}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11115839}, issn = {0964-6906}, year = {2000}, date = {2000-12-01}, journal = {Human molecular genetics}, volume = {9}, number = {20}, pages = {2959--65}, abstract = {We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs. |
Lampis, R; Morelli, L; Congia, M; Macis, M D; Mulargia, A; Loddo, M; De Virgiliis, S; Marrosu, M G; Todd, J A; Cucca, F The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases. Journal Article Hum Mol Genet, 9 (20), pp. 2959–2965, 2000, ISSN: 0964-6906 0964-6906. |