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1. A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers

Author

Munir Pirmohamed, Guruprasad P. Aithal, Felix Stickel, Mark Thursz, David Goldman, Paul S. Haber, John Whitfield, Romain Moirand, Bertrand Nalpas, Devanshi Seth, Christophe Moreno, Andrew Thompson, Eric Trepo, Stephen R. Atkinson, Rebecca Darlay, Beat Müllhaupt, Timothy R. Morgan, Dermot Gleeson, Sylvie Naveau, Ann K. Daly, Helmut K. Seitz, Michael Soyka, Christopher P. Day, Tatiana Foroud, Jean-Marc Jacquet, Laura E. Nagy, Naga Chalasani, Pascal Perney, Philippe Mathurin, Marsha Y. Morgan, Pierre Nahon, Sebastian Mueller, Tiebing Liang, Florian Eyer, Suthat Liangpunsakul, Heather J. Cordell, Steven Masson, Tae-Hwi Schwantes-An, Ramon Bataller, Greg Botwin, Andrew McQuillin, QIMR Berghofer Medical Research Institute, Indiana University School of Medicine, Indiana University System, Newcastle University [Newcastle], University of Nottingham, UK (UON), Imperial College London, University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), California State University [Long Beach] (CSULB ), Indiana University - Purdue University Indianapolis (IUPUI), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health [Bethesda] (NIH), The University of Sydney, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Claude Huriez [Lille], CHU Lille, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University College of London [London] (UCL), Université libre de Bruxelles (ULB), University of Heidelberg, Medical Faculty, University hospital of Zurich [Zurich], Lerner Research Institute, Cleveland Clinic, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of Liverpool, University-Hospital Munich-Großhadern [München], University of California, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lerner Research Institute [Cleveland, OH, USA], University of California (UC), Technical University of Munich (TUM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Liver Cirrhosis, Male, Cirrhosis, Hepatocellular carcinoma, [SDV]Life Sciences [q-bio], Alcohol, Disease, risk stratification, Gastroenterology, Oral and gastrointestinal, Cohort Studies, Liver disease, Alcohol Use and Health, Substance Misuse, chemistry.chemical_compound, 0302 clinical medicine, Liver Cirrhosis, Alcoholic, single nucleotide polymorphism, Cancer, 2. Zero hunger, 0303 health sciences, Framingham Risk Score, genome wide association, Liver Disease, Single Nucleotide, Middle Aged, Alcoholic, 3. Good health, Alcoholism, Public Health and Health Services, 030211 gastroenterology & hepatology, Female, Risk assessment, Liver Cancer, Adult, medicine.medical_specialty, Alcohol Drinking, Chronic Liver Disease and Cirrhosis, Clinical Sciences, coffee, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, GenomALC Consortium, Rare Diseases, Clinical Research, Diabetes mellitus, Internal medicine, Genetics, Diabetes Mellitus, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Metabolic and endocrine, 030304 developmental biology, Gastroenterology & Hepatology, Hepatology, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Odds ratio, medicine.disease, chronic alcohol use, Good Health and Well Being, chemistry, Case-Control Studies, genome-wide association, Digestive Diseases, business, Body mass index, Genome-Wide Association Study
Abstract

International audience; BACKGROUND and AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to eight genetic loci identified previously as associated with alcohol-related cirrhosis and three clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of three single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated for cirrhosis risk. The odds ratio (OR) and 95% confidence intervals (CI) for the extreme score quintiles (Q1-Q5) of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18;8.60) (GenomALC-1); 2.81 (2.03;3.89) (GenomALC-2); and 3.10 (2.32;4.14) (UK Biobank). Patients with diabetes and high-risk score, compared to those without diabetes and a low-risk score, had ORs increased to 14.7 (7.69;28.1) (GenomALC-1) and 17.1 (11.3;25.7) (UK Biobank). Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76±0.06 versus 0.61±0.02, p=0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on three genetic risk variants and diabetes status can provide meaningful risk stratification for cirrhosis in excess drinkers, allowing earlier prevention planning including intensive intervention. LAY SUMMARY: Excessive chronic drinking leads to liver cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. Our study has developed a genetic risk score (GRS) test that can identify patients at high risk and shows that the risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and high GRS. Risk assessment using this test has potential for early and personalised management of this disease in high-risk patients.

Published
2021
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2. Genome-wide association study and meta-analysis on alcohol-related liver cirrhosis identifies novel genetic risk factors

Author

Sebastian Mueller, Tiebing Liang, Pierre Nahon, Florian Eyer, Suthat Liangpunsakul, Devanshi Seth, Michael Soyka, Romain Moirand, David Goldman, Sylvie Naveau, Timothy R. Morgan, Beat Muellhaupt, Pascal Perney, Jean-Marc Jacquet, Helmut K. Seitz, Heather J. Cordell, Munir Pirmohamed, Guruprasad P. Aithal, Felix Stickel, Christopher P. Day, Philippe Mathurin, Dermot Gleeson, Paul S. Haber, Greg Botwin, John Whitfield, Steven Masson, Tae-Hwi Schwantes-An, Ann K. Daly, Bertrand Nalpas, Andrew Thompson, Rebecca Darlay, Tatiana Foroud, Lawrence Lumeng, Indiana University System, Newcastle University [Newcastle], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Heidelberg, Medical Faculty, University of Nottingham, UK (UON), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Royal Hallamshire Hospital, University of Liverpool, University hospital of Zurich [Zurich], Klinikum der Universität [München], Service Addictologie [CHU Nîmes] (Pôle ICAGNE), Hôpital Universitaire de Réadaptation, de Rééducation et d'Addictologie du CHU de Nîmes [Grau-du-Roi] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Antoine Béclère [Clamart], Veterans Affairs Long Beach Healthcare System (VA Long Beach Healthcare System), NSW Government, The University of Sydney, QIMR Berghofer Medical Research Institute, U01‐AA018389, National Institute on Alcohol Abuse and Alcoholism, APP1155320, National Health and Medical Research Council, Swiss Foundation for Alcohol Research, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Jonchère, Laurent, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, FAF2, [SDV]Life Sciences [q-bio], Genome-wide association study, Locus (genetics), Biology, lipid droplet pathway, HSD17B13, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Liver Cirrhosis, Alcoholic, Risk Factors, Databases, Genetic, medicine, Humans, Genetic Predisposition to Disease, Allele, PNPLA3, 030304 developmental biology, 2. Zero hunger, Genetics, 0303 health sciences, Hepatology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Odds ratio, Middle Aged, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, [SDV] Life Sciences [q-bio], Meta-analysis, 030211 gastroenterology & hepatology, Female, Body mass index, TM6SF2, Genome-Wide Association Study, α1-antitrypsin
Abstract

International audience; Background and aims - Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and results - We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions - Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

Published
2021
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3. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis

Author

Matej Orešič, Fabio Marra, Christopher P. Day, Federico Ravaioli, Katherine Johnson, Elisabetta Bugianesi, Jérôme Boursier, Pierre Bedossa, Olivier Govaere, Rebecca Darlay, Salvatore Petta, Jeremy M. Palmer, Quentin M. Anstee, Ramy Younes, Heather J. Cordell, Rachel Queen, Jörn M. Schattenberg, Ann K. Daly, Mattias Ekstedt, Dina Tiniakos, Leigh Alexander, Michele Vacca, Antonio Vidal-Puig, Chiara Rosso, Karine Clément, Michael Allison, Vlad Ratziu, Kristy Wonders, Simon Cockell, Bioinformatics Support Unit, Newcastle University [Newcastle], Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Govaere O., Cockell S., Tiniakos D., Queen R., Younes R., Vacca M., Alexander L., Ravaioli F., Palmer J., Petta S., Boursier J., Rosso C., Johnson K., Wonders K., Day C.P., Ekstedt M., Oresic M., Darlay R., Cordell H.J., Marra F., Vidal-Puig A., Bedossa P., Schattenberg J.M., Clement K., Allison M., Bugianesi E., Ratziu V., Daly A.K., and Anstee Q.M.

Subjects
0301 basic medicine, Liver Cirrhosis, Cirrhosis, [SDV]Life Sciences [q-bio], Disease, Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, nash, Non-alcoholic Fatty Liver Disease, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, Diabetes Mellitus, Humans, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, Diabetes Mellitus, Type 2, Liver, Immunology, 030211 gastroenterology & hepatology, GDF15, Steatohepatitis, Type 2
Abstract

International audience; The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409 , a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort ( n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10 , GDF15 , and PDGFA , whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.

Published
2020
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4. Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Author

Colin G. Miles, Heather J. Cordell, Simon A. Ramsbottom, Meral Gunay-Aygun, Shirlee Shril, Elisa Molinari, John A. Sayer, Helena L. Spiewak, Laura A. Devlin, Peter E. Thelwall, Sophie Saunier, Flora Silbermann, Friedhelm Hildebrandt, Katrina M Wood, Gavin J. Clowry, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Harvard Medical School [Boston] (HMS), National Human Genome Research Institute (NHGRI), Johns Hopkins University School of Medicine [Baltimore], and Saunier, Sophie

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Severity of Illness Index, Retina, Joubert syndrome, Mice, 03 medical and health sciences, Cystic kidney disease, Antigens, Neoplasm, Chloride Channels, Cerebellum, medicine, Animals, Abnormalities, Multiple, Genetic Predisposition to Disease, genetics, Eye Abnormalities, Barttin, Genetics, Cystic kidney, modifier, Genes, Modifier, Multidisciplinary, Genetic heterogeneity, Biological Sciences, Kidney Diseases, Cystic, medicine.disease, Phenotype, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Cytoskeletal Proteins, Disease Models, Animal, Ciliopathy, 030104 developmental biology, ciliopathy, Mutation, Kidney Diseases, Rare disease, Kidney disease
Abstract

Significance Our current understanding of genetic disease is often inadequate, largely due to genetic background effects that modify disease presentation. This is particularly challenging for rare diseases that lack sufficient numbers of patients for genome-wide association studies. We show in a series of experiments using a murine model of Joubert syndrome, a multisystem ciliopathy, that a single locus is a modifier of cystic kidney disease. We go on to show that the human homolog plays a similar role in disease using a cohort of patients. These findings make a significant contribution to the underplayed (and often ignored) role of genetic background in murine models and how this can be exploited to understand further rare inherited disease., Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.

Published
2020
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5. Enabling the genomic revolution in Africa

Author

Anh Quynh Nguyen, Daniel T. Lackland, Gustave Simo, Oumar Samassekou, Lukman Owolabi, Faisal M. Fadlelmola, Matthias Kretzler, Victoria Adabayeri, Jeffrey B. Kopp, Mary T Mayige, Mark S. Guyer, Charlotte Osafo, Nigel J. Crowther, Winston Hide, Eyitayo Fakunle, Guillaume Paré, Issa Sidibe, Bamidele O. Tayo, Manmak Mamven, Stephen Tollman, Christian T. Happi, Anne Fischer, James A. G. Whitworth, Andrew Tareila, Moses Joloba, Kristian G. Andersen, Odile Ouwe Missi Oukem-Boyer, Paul L. Kimmel, Thuli Mthiyane, Anita Ghansah, Sylvester Leonard Lyantagaye, T O Olanrewaju, John Enyaru, Kwamena W. Sagoe, Maia Lesosky, Neil A. Hanchard, Rita T. Lawlor, Ellis Owusu-Dabo, Eileen Obe, Shiksha Reddy, Margaret B. Penno., Rembert Pieper, Maria Y. Giovanni, Louise Wideroff, Yasmina Jaufeerally-Fakim, Marape Marape, Stacy Carrington-Lawrence, Oyekanmi Nash, Dwomoa Adu, Rebekah S. Rasooly, Rajkumar Ramesar, Mukthar Kader, Carolyn Jenkins, Simani Gaseitsiwe, Michèle Ramsay, Betty Nsangi, Olukemi K. Amodu, Mark P. Nicol, Adeodata Kekitiinwa, Thomas Lehner, Nzovu Ulenga, Saidi Kapiga, Victor Jongeneel, Gebregziabher Mulugeta, Nathan L. Yozwiak, Gabriel Anabwani, Solomon F. Ofori-Acquah, Misaki Wayengera, Rasheed Bakare, Marianne Alberts, Jantina de Vries, Robert F. Garry, Marsha Treadwell, Robert Kleta, Eugene Sobngwi, Ezra Susser, Mo Nagdee, Carmen Swanepoel, Osman Sankoh, Masego Tsimako-Johnstone, Godfred Tangwa, Zané Lombard, Darren P. Martin, Donald S. Grant, Bernard Keavney, Mahamadou Traoré, Ahmed El Sayed, Seth O. McLigeyo, Charles Mondo, Dan J. Stein, Özlem Tastan Bishop, Jane Peterson, Ute Jentsch, Moffat Nyirenda, Charles N. Rotimi, Shane A. Norris, Chengetai R. Mahomva., Gobena Ameni, Sheryl A. McCurdy, M Boehnke, Sally N Akarolo-Anthony, Oumou Sow Bah, Muntaser E. Ibrahim, Ishmael Kasvosve, Dean Everett, Kathleen Kahn, S.W.O. Ogendo, Abraham Oduro, Cheryl A. Winkler, Robin Mason, Orlando Alonso Betancourt, Hugh-G. Patterton, Heather J. Zar, John Oli, Audrey Duncanson, Daouda Ndiaye, Alan Christoffels, Adebowale Adeyemo, Kenneth H. Fischbeck, Manjinder S. Sandhu, Kwaku Ohene-Frempong, Samuel Ajayi, Chester W. Brown, Godfred Agongo, Tunde Salako, Ablo Prudence Wachinou, Gasnat Shaboodien, Pardis C. Sabeti, Jean Claude Mbanya, Peter Donkor, Dieuodonne Mumba, Heather J. Cordell, Sarah Winnicki, Reginald Obiakor, Fourie Joubert, Samar K. Kassim, Mark I. McCarthy, Scott Hazelhurst, Pontiano Kaleebu, Richard S. Cooper, Jennifer L. Troyer, Hermann Sorgho, Oyedunni Arulogun, Ravnit Grewal, Bongani M. Mayosi, Jacob Plange-Rhule, Christiane Hertz-Fowler, Alia Benkahla, Okechukwu S Ogah, Akin Abayomi, Mayowa O. Owolabi, Mark E Engel, Rufus Akinyemi, Ezekiel Adebiyi, Alash'le Abimiku, John Chisi, Patricia A. Marshall, Bruce Ovbiagele, Catherine Kyobutungi, Ambroise Wonkam, Vincent Tukei, David T. Burke, Fred Stephen Sarfo, Andrew Owen, Julie Makani, Leslie Derr, Mary Claire King, Nicki Tiffin, Vincent Boima, Barrington G. Burnett, Martin Simuunza, Christine Beiswanger, Nicola Mulder, Ekaete Tobin, Katherine Littler, Frank C. Brosius, Rulan S. Parekh, Halidou Tinto, Talishiea Croxton, Onikepe A. Folarin, Seydou Doumbia, Parham Goesbeck, Salina P. Waddy, Andrew Brooks, Marva Moxey-Mims, Guida Landouré, Marie Sarr, Martin R. Pollak, Akinlolu O. Ojo, Danny Asogun, Beverley van Rooyen, Clement Adebamowo, Jeanne F. Loring, Naomi S. Levitt, Jonathan K. Kayondo, Nadia Carstens, John V. Moran, F. Xavier Gómez-Olivé, John Musuku, Enock Matovu, Ifeoma Ulasi, Alisha N. Wade, Regina James, Ebony B. Madden, Liam Smeeth, Friedhelm Hilderbrandt, James Brandful, Chisomo L. Msefula, Christopher Hugo-Hamman, Annette MacLeod, Lara Bethke, Judit Kumuthini, Julia Puzak, Mengistu Tadase Yewondwossen, Sudha Srinivasan, Sheik Humarr Khan, Daniel K. Masiga, Mathurin Koffi, Oathokwa Nkomazana, Sununguko Wata Mpoloka, Fatiu A Arogundade, Dissou Affolabi, Ahmed M. Alzohairy, Ayesha A. Motala, Pan Pan Jiang, Adebowale D. Ademola, Ana Olga Mocumbi, Samuel Kyobe, Graeme Mardon, Albert Akpalu, Karen A. Lacourciere, Himla Soodyall, Branwen J. Hennig, Bruno Bucheton, Naby Balde, Michael Mate-Kole, Alexander K. Nyarko, Helen McIlleron, Mary Lynn Baniecki, Ivy Ekem, Corrine Merle, Rasheed Gbadegesin, Junaid Gamieldien, Makerere University [Kampala, Ouganda] (MAK), Institut de Recherche pour le Développement (IRD), University of Malawi, University of Liverpool, Université Jean Lorougnon Guédé (UJloG ), University of Glasgow, Institut National de Recherche Biomédicale [Kinshasa] (INRB), Centre international de recherche-développement sur l'élevage en zone sub-humide (CIRDES), Université de Dschang, University of Zambia [Lusaka] (UNZA), University of Cape Town, University of Nairobi (UoN), Instituto Nacional de Saude [Maputo, Mozambique] (INS), Windhoek Central Hospital [Namibie], University College Hospital [Ibadan, Nigeria], Alzaiem Alazhari University [Soudan] (AAU-Sudan), Mulago Hospital [Kampala, Ouganda], Newcastle University [Newcastle], McMaster University [Hamilton, Ontario], University of Manchester [Manchester], Nelson R Mandela School of Medicine [Durban, South Africa] (NRMSM), University of KwaZulu-Natal (UKZN), University of Yaoundé [Cameroun], Medical Research Council Unit The Gambia (MRC), Hôpital Donka, Ministère de la Santé [Conakry, Guinea], Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), Liverpool School of Tropical Medicine (LSTM)-University of Liverpool-Wellcome Trust-University of Malawi, University of Nigeria, Institute of Human Virology [Nigeria] (IHVN), National Institute for Medical Research [Tanzania] (NIMR), MRC/UVRI & LSHTM Uganda Research Unit, Medical Research Council-London School of Hygiene and Tropical Medicine (LSHTM)-Medical Research Council Unit The Gambia (MRC)-Uganda Virus Research Institute (UVRI), The Wellcome Trust Sanger Institute [Cambridge], London School of Hygiene and Tropical Medicine (LSHTM), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], National Human Genome Research Institute (NHGRI), Institut Pasteur de Tunis, and Réseau International des Instituts Pasteur (RIIP)

Subjects
MESH: Health, [SDV]Life Sciences [q-bio], MEDLINE, Genomics, Genome-wide association study, Computational biology, Biology, MESH: Africa, 03 medical and health sciences, 0302 clinical medicine, MESH: England, Research capacity, MESH: Disease/genetics, MESH: United States, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Multidisciplinary, MESH: Humans, business.industry, MESH: Genomics/trends, Biotechnology, MESH: Genome-Wide Association Study/trends, MESH: Genetics, Medical/trends, business, MESH: National Institutes of Health (U.S.)
Abstract

H3Africa is developing capacity for health-related genomics research in Africa

Published
2014
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6. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Author

Doris Lechner, Miriam Capri, Stefan Böhringer, Stefan Schreiber, Gonneke Willemsen, Paolo Garagnani, Irene Maeve Rea, Andres Metspalu, Palmi V. Jonsson, Thomas B. L. Kirkwood, Lene Christiansen, Fernando Rivadeneira, Giuseppina Rose, J. Wouter Jukema, Serena Dato, Owen A. Ross, Almut Nebel, Cornelia M. van Duijn, Gary Saunders, Bernard Jeune, David J. Stott, Jeanine J. Houwing-Duistermaat, A. Murphy, Anton J. M. de Craen, Friederike Flachsbart, Karen Andersen-Ranberg, Albert Hofman, Ian Ford, Ellen A. Nohr, Giuseppe Passarino, Krista Fischer, Elisa Cevenini, Carmen Martin-Ruiz, Jutta Gampe, Iris Postmus, Christopher P. Nelson, Stefano Salvioli, Alberto Montesanto, Mark Lathrop, Marianne Nygaard, Marie E. Breen, Jennifer Harrow, Hae-Won Uh, Erik B. van den Akker, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexander Viktorin, Bastiaan T. Heijmans, Susan E. McNerlan, Quinta Helmer, Naveed Sattar, Claudio Franceschi, Eco J. C. de Geus, E. Mihailov, Jouke-Jan Hottenga, Qihua Tan, Kari Stefansson, Yoichiro Kamatani, Paolina Crocco, Henning Tiemeier, Stella Trompet, Patrik K. E. Magnusson, Marian Beekman, Riin Tamm, Amke Caliebe, Maris Alver, Femke-Anouska Heinsen, Pilar Galan, Daníel F. Guðbjartsson, Joris Deelen, Linda Broer, Ruud van der Breggen, Kristin L. Ayers, Anna M. Bennet, Dorret I. Boomsma, P. Eline Slagboom, Kaare Christensen, Diana van Heemst, Joanna Collerton, Karen Davies, Rudi G. J. Westendorp, Hélène Blanché, Lavinia Paternoster, Nilesh J. Samani, Hreinn Stefansson, Simon P. Mooijaart, Heather J. Cordell, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), LeidenUniversity Medical Centre, Department of Epidemiology, The Netherlands Cancer Institute, Institute of Genetic Medicine, Newcastle University [Newcastle], National Institute of Public Health, University of Southern Denmark (SDU), Department of Clinical Genetics, Odense University Hospital, Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Tartu, Institute of Molecular and Cell Biology, Department of Gerontology and Geriatrics, Leiden University Medical Center (LUMC), deCODE genetics [Reykjavik], Christian-Albrechts University of Kiel, University of Calabria, Delft University of Technology (TU Delft), Department of Cardiovascular Sciences, Université Catholique de Louvain = Catholic University of Louvain (UCL), University Hospitals Leicester, Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Iowa [Iowa City], DIMES: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University Hospital, Institute for Ageing and Health, University of Glasgow, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO Institute for Health and Care Research, VU University Amsterdam Medical Center, Landspitali National University Hospital of Iceland, University of Iceland, McGill University = Université McGill [Montréal, Canada], Genome Quebec Innovation Centre, Institut de Génomique, Belfast Health and Social Care Trust, Estonian Biocentre, Partenaires INRAE, Aarhus University [Aarhus], School of Social and Community Medicine, Erasmus University Rotterdam, Mayo Clinic, BHF Glasgow Cardiovascular Research Centre, University Medical Center Schleswig-Holstein, Institute of Cardiovascular and Medical Sciences, Sophia Children's Hospital, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Augustinus Foundation, Avera Institute for Human Genetics (AIHG), AXA Research Fund, Belfast City Hospital Trust Fund, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007], Biotechnology and Biological Sciences Research Council (BBSRC), Bristol-Myers Squibb, Center for Inherited Disease Research (CIDR), Centre for Medical Systems Biology (CMSB), CERA Foundation, Commissariat a L'Energie Atomique (CEA)-Centre National de Genotypage (CNG), Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR) [11-107308], Danish National Research Foundation (DNRF), Department of Health and Social Services (Northern Ireland), DFG-Cluster of Excellence 'Inflammation at Interfaces', Dunhill Medical Trust [R124/0509], Egmont Foundation, Estonian Science Foundation [7859], Estonian Government [SF0180142s08], European Research Council (ERC) [230374], European Science Foundation (ESF) [EU/QLRT-2001-01254], European Union [FP5-QLK6-CY-2001-00128, FP6-LIFESCIHEALTH-36894, FP6-LSH M-CT-2004-503270, FP7-HEALTH-2007-B-223004, FP7-HEALTH-F4-2007-201413, FP7-HEALTH-F4-2008-202047, FP7-HEALTH-2009-single-stage-242244, FP7-HEALTH-2010-two-stage-259679], Fondation Caisse d'Epargne Rhone-Alpes Lyon CERAL, Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH) [MH081802], GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254], Guy's & St Thomas' NHS Foundation Trust, Health Foundation, Heart and Lung foundation [20070481], Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007], Institut National de la Recherche Agronomique (INRA), Institut National de la Sante et de la Recherche Medicale (INSERM), King's College London, Medical Research Council (MRC) [G0500997, G0601333], Ministere de l'Enseignement superieur et de la Recherche (MESR), National Institutes of Health (NIH)/National Institute of Aging (NIA) [P01AG08761, R01D0042157-01A, U01DK066134], National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre, NBIC BioAssist [NWO-NBIC/BioAssist/RK/2008.024], Netherlands Consortium for Healthy Ageing (NCHA) [050-060-810], Netherlands Genomics Initiative (NGI), Netherlands Heart Foundation (NHF) [2001 D 032], Netherlands Organization for Scientific Research (NWO, MagW/ZonMW) [904-61-090, 904-61-193, 480-04-004, 400-05-717, Spinozapremie 56-464-14192, 175.010.2005.011, 911-03-012, 985-10-002, Addiction-31160008, Middelg-root-911-09-032], Netspar - Living longer for a good health, NHS North of Tyne (Newcastle Primary Care Trust), Pharmacy Foundation, Regione Autonoma della Sardegna, Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06], Swedish Research Council [M-2005-1112], Tampere University Hospital and Academy of Finland, Danish Interdisciplinary Research Council, Health Foundation (Helsefonden), Ministry for Higher Education, National Program for Research Infrastructure [09-063256], March of Dimes Birth Defects Foundation, Swedish Foundation for Strategic Research (SSF), Unilever Discover Colworth, Universite Paris 13, University of Tartu [SP1GVAR-ENG], Velux Foundation, VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), Wellcome Trust [084762, 085475, 087436], IDEAL [FP7-HEALTH-2010-two-stage-259679], Research and Education into Ageing-0153, European Regional Development Fund, Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guðbjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, van den Akker EB, Böhringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJ, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, McNerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefánsson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RG, Willemsen G, Samani NJ, Galan P, Sørensen TI, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJ, Christensen K, Nebel A, Stefánsson K, Metspalu A, Magnusson P, Blanché H, Christiansen L, Kirkwood TB, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, Slagboom PE., Leiden Univ, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands [ 2 ] Leiden Univ, Netherlands Consortium Healthy Ageing, NL-2300 RC Leiden, Netherlands [ 3 ] Leiden Univ, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands [ 4 ] Leiden Univ, Dept Cardiol, NL-2300 RC Leiden, Netherlands [ 5 ] Leiden Univ, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands [ 6 ] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands [ 7 ] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands [ 8 ] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England [ 9 ] Univ So Denmark, Inst Publ Hlth, DK-5000 Odense C, Denmark [ 10 ] Univ So Denmark, Inst Clin Res, Dept Gynecol & Obstet, DK-5000 Odense C, Denmark [ 11 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 12 ] Odense Univ Hosp, Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark [ 13 ] Fdn Jean Dausset CEPH, F-75010 Paris, France [ 14 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 15 ] Univ Tartu, Estonian Genome Ctr, Tartu 51010, Estonia [ 16 ] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia [ 17 ] deCODE Genet, Populat Gen, IS-101 Reykjavik, Iceland [ 18 ] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany [ 19 ] Univ Kiel, Inst Med Informat & Stat, D-24105 Kiel, Germany [ 20 ] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy [ 21 ] Delft Univ Technol, Delft Bioinformat Lab, NL-2600 GA Delft, Netherlands [ 22 ] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England [ 23 ] Glenfield Hosp, Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester LE3 9QP, Leics, England [ 24 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England [ 25 ] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland [ 26 ] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA [ 27 ] Univ Bologna, Dept Expt Diagnost & Specialty Med, I-40126 Bologna, Italy [ 28 ] Univ Bologna, Interdepartmental Ctr L Galvani, I-40126 Bologna, Italy [ 29 ] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England [ 30 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland [ 31 ] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland [ 32 ] Max Planck Inst Demograf Forsch, Lab Stat Demog, D-18057 Rostock, Germany [ 33 ] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands [ 34 ] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands [ 35 ] Landspitali Univ Hosp, IS-101 Reykjavik, Iceland [ 36 ] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland [ 37 ] CEA, Inst Genom, F-91057 Evry, France [ 38 ] McGill Univ, Montreal, PQ H3G 1A4, Canada [ 39 ] Genome Quebec Innovat Ctr, Montreal, PQ H3G 1A4, Canada [ 40 ] Belfast Hlth & Social Care Trust, Cytogenet Lab, Belfast BT8 8BH, Antrim, North Ireland [ 41 ] Estonian Bioctr, EE-51010 Tartu, Estonia [ 42 ] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, DK-8000 Aarhus C, Denmark [ 43 ] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England [ 44 ] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA [ 45 ] Univ Glasgow, Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland [ 46 ] Univ Kiel, PopGen Biobank, D-24105 Kiel, Germany [ 47 ] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany [ 48 ] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CA Rotterdam, Netherlands [ 49 ] Univ Paris 04, UREN, U557, INSERM, F-93017 Bobigny, France [ 50 ] U1125 Inra, F-93017 Bobigny, France [ 51 ] Cnam, F-93017 Bobigny, France [ 52 ] Univ Paris 13, CRNH IdF, F-93017 Bobigny, France [ 53 ] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr, DK-2200 Copenhagen N, Denmark [ 54 ] Inst Prevent Med, DK-2000 Copenhagen, Denmark [ 55 ] Frederiksberg Univ Hosp, DK-2000 Copenhagen, Denmark [ 56 ] Interuniv Cardiol Inst Netherlands, NL-3501 DG Utrecht, Netherlands [ 57 ] Bellaria Hosp, IRCCS Inst Neurol Sci, I-40139 Bologna, Italy [ 58 ] CNR, ISOF, I-40129 Bologna, Italy, Epidemiology, Surgery, Internal Medicine, Child and Adolescent Psychiatry / Psychology, ProdInra, Migration, Vrije Universiteit Amsterdam [Amsterdam] (VU), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Amsterdam, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes

Subjects
Male, Netherlands Twin Register (NTR), Disease/genetics, Lífslíkur, Longevity/genetics, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetic Linkage, Genome-wide association study, 0302 clinical medicine, Prospective Studies, Genetics (clinical), Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Association Studies Articles, Age Factors, Chromosome Mapping, Genetic Loci/physiology, General Medicine, 3. Good health, Europe, Phenotype, Cardiovascular Diseases, Hypertension, Chromosomes, Human, Pair 5, Female, Human Longevity, genetics, meta-analysis, Aging/genetics, Cardiology and Cardiovascular Medicine, HUMAN AGING, Longevity, European Continental Ancestry Group, Population, HUMAN GENETICS, Single-nucleotide polymorphism, Locus (genetics), Biology, FAMILIAL LONGEVITY, White People, 03 medical and health sciences, Gene mapping, SDG 3 - Good Health and Well-being, Cardiovascular Diseases/genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Allele, education, Molecular Biology, Aged, 030304 developmental biology, Genetic association, Öldrun, Genome, Human, Arfgengi, Minor allele frequency, Ageing, Genetic Loci, Chromosomes, Human, Pair 19, Hypertension/genetics, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (

Published
2014
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7. Dealing with missing data in family-based association studies: a multiple imputation approach

Author

Heather J. Cordell, Emmanuelle Génin, Pascal Croiseau, Vaillant, Christine, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Human Genetics (NEWCASTLE UNIVERSITY), Newcastel University, and ARSEP

Subjects
haplotype, Genotype, multiple imputation, Computer science, Posterior probability, [SDV.GEN] Life Sciences [q-bio]/Genetics, 01 natural sciences, Article, 010104 statistics & probability, 03 medical and health sciences, missing data, Statistics, Genetics, Odds Ratio, Humans, Family, Genetic Predisposition to Disease, Imputation (statistics), 0101 mathematics, Genetics (clinical), 030304 developmental biology, conditional logistic regression, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Models, Statistical, business.industry, Usability, Replicate, Missing data, Quantitative Biology::Genomics, Confidence interval, Haplotypes, Sample size determination, Case-Control Studies, Data Interpretation, Statistical, Regression Analysis, business, case-parent trio, Type I and type II errors
Abstract

International audience; To test for association between a disease and a set of linked markers, or to estimate relative risks of disease, several different methods have been developed. Many methods for family data require that individuals be genotyped at the full set of markers and that phase can be reconstructed. Individuals with missing data are excluded from the analysis. This can result in an important decrease in sample size and a loss of information. A possible solution to this problem is to use missing-data likelihood methods. We propose an alternative approach, namely the use of multiple imputation. Briefly, this method consists in estimating from the available data all possible phased genotypes and their respective posterior probabilities. These posterior probabilities are then used to generate replicate imputed data sets via a data augmentation algorithm. We performed simulations to test the efficiency of this approach for case/parent trio data and we found that the multiple imputation procedure generally gave unbiased parameter estimates with correct type 1 error and confidence interval coverage. Multiple imputation had some advantages over missing data likelihood methods with regards to ease of use and model flexibility. Multiple imputation methods represent promising tools in the search for disease susceptibility variants.

Published
2007

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