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Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

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Figure 1: Distribution of Z scores from the stage 2 meta-analysis, aligned to the risk allele from stage 1.
Figure 2: Regional plots of T2D susceptibility loci with evidence of multiple association signals.
Figure 3: Functional analyses.

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Acknowledgements

Funding for this study was provided by the Academy of Finland (77299, 102318, 110413, 118065, 123885, 124243, 129680, 129293, 129494, 136895, 139635, 141005, 213506 and 251217); Agence Nationale de la Recherche (France); the American Diabetes Association (7-08-MN-OK); Association Française des Diabétiques; Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques (France); Association Diabète Risque Vasculaire (France); British Diabetic Association (BDA) Research (UK); the British Heart Foundation (RG/98002 and RG2008/08); Cancer Research UK; the Central Norway Health Authority; the Central Finland Hospital District; the Center for Inherited Disease Research (CIDR) (USA); the Chief Scientist Office, Scotland (CZB/4/672); the City of Kuopio (Finland); the City of Leutkirch (Germany); the Department of Health (UK); Deutsche Forschungsgemeinschaft (ER1 55/6-2); Diabetes UK; the Doris Duke Charitable Foundation (USA); the Estonian government (SF0180142s0); the European Commission: ENGAGE (HEALTH-F4-2007- 201413), EXGENESIS (LSHM-CT-2004-005272), 245536, QLG1-CT-2002-00896 and 2004310; the European Commission (Marie Curie: FP7-PEOPLE-2010-IEF); the European Regional Development Fund; the Faculty of Medicine at the Norwegian University of Science and Technology; the Finnish Diabetes Association; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Heart Association; the Finnish Medical Society; the Folkhälsan Research Foundation (Finland); the Food Standards Agency (UK); the Foundation for Life and Health in Finland; the Federal Ministry of Education and Research (BMBF) (Germany); the Federal Ministry of Health (Germany); the General Secretary of Research and Technology (Greece); the German Center for Diabetes Research (DZD); the German Research Council (GRK 1041); the Great Wine Estates of the Margaret River region of Western Australia; Groupe d'Etude des Maladies Métaboliques et Systémiques (France); Harvard Medical School (USA); the Heinz Nixdorf Foundation (Germany); Helmholtz Zentrum München–Research Center for Environment and Health (Germany); the Helsinki University Central Hospital Research Foundation (Finland); IngaBritt and Arne Lundberg's Research Foundation (Sweden) (grant 359); the Ministry of Health (Ricerca Corrente) (Italy); Karolinska Institutet (Sweden); the Knut and Alice Wallenberg Foundation (Sweden) (KAW 2009.0243); Kuopio University Hospital (Finland); the Municipal Heath Care Center and Hospital, Jakobstad, Finland; the Ministry of Social Affairs and Health (Finland); the Ministry of Education and Culture (Finland) (627; 2004–2011); the Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia (Germany); the Medical Research Council (UK) (G0000649 and G0601261); an MRC-GSK pilot programme grant (UK); the Munich Center of Health Sciences (MC Health) (Germany); the National Genome Research Network (NGFN) (Germany); the National Heart, Lung, and Blood Institute (NHLBI) (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N01HC25195 and N02HL64278); the National Human Genome Research Institute (NHGRI) (U01HG004402 and N01HG65403); the US National Institutes of Health (USA) (HHSN268200625226C, UL1RR025005, U01HG004399, 1R21NS064908, 1Z01HG000024, AG028555, AG08724, AG04563, AG10175, AG08861 and CA055075); the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK062370, DK058845, DK072193, DK078616, DK080140 and DK073490); the Närpes Health Care Foundation (Finland); the National Health Screening Service of Norway; the National Institute of Health Research (UK); the National Institute for Health and Welfare (Finland); the Nord-Trøndelag County Council (Norway); the Nordic Center of Excellence in Disease Genetics; the Norwegian Institute of Public Health; the Norwegian Research Council; Novo Nordisk Fonden (Denmark); the Ollqvist Foundation (Sweden); the Oxford NIHR Biomedical Research Centre (UK); the Paavo Nurmi Foundation (Finland); the Päivikki and Sakari Sohlberg Foundation (Finland); the Perklén Foundation (Sweden); Pfizer; the Pirkanmaa Hospital District (Finland); Programme National de Recherche sur le Diabète (France); Programme Hospitalier de Recherche Clinique (French Ministry of Health); the Region of Nord-Pas-de-Calais (Contrat de Projets Etat-Région) (France); Research into Ageing (UK); the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; the Royal Swedish Academy of Sciences; Sarstedt AG & Co. (Germany); the Signe and Ane Gyllenberg Foundation (Sweden); the Slottery Machine Association (Finland); the Social Insurance Institution of Finland (4/26/2010); the South OstroBothnia Hospital District (Finland); the State of Baden-Württemberg, Germany; the Stockholm County Council (560183 and 562183); Stroke Association (UK); the Swedish Research Council (8691, 09533, 2009-1039, Dnr 521-2010-3490, Dnr 521-2007-4037, Dnr 521-2008-2974, Dnr 825-2010-5983 and Dnr 349-2008-6589); the Swedish Cultural Foundation in Finland; the Swedish Diabetes Foundation; the Swedish Heart-Lung Foundation; the Swedish Foundation for Strategic Research; the Swedish Society of Medicine; the Swedish Research Council; the Swedish Research Council for Infrastructures; The Sigrid Juselius Foundation (Finland); the Torsten and Ragnar Söderberg Foundation (Sweden) (MT33/09); University Hospital Essen (Germany); University of Tromsø (Norway); Uppsala University (Sweden); Uppsala University Hospital (Sweden); and the Wellcome Trust (GR072960, 076113, 077016, 081682, 083948, 083270, 084711, 086596, 090367, 090532 and 098051). A more detailed set of acknowledgments is provided in the Supplementary Note.

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Writing group: A.P.M., B.F.V., T.M.T., T. Ferreira, A.V.S., V. Steinthorsdottir, R.J.S., H.K., H.G., A. Mahajan, I.P., M.B. and M.I.M.

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Correspondence to Andrew P Morris, Michael Boehnke or Mark I McCarthy.

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Competing interests

V.S., G.T., U.T. and K.S. are employees at deCODE genetics, a biotechnology company that provides genetic testing services, and own stock and/or stock options in the company. J.F. received consulting honoraria from Novartis, Eli Lilly and Pfizer. I.B. and spouse own stock in GlaxoSmithKline and Incyte.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44, 981–990 (2012). https://doi.org/10.1038/ng.2383

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