Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. HofmannJosée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy Van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noisël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S F Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R B Perry, Ann Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. Van Dam, Timon W. Van Haeften, Thijs Van Herpt, Jana V. Van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N A Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Gonçalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H. Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Thomas Illig, Philippe Froguel, Cornelia M. Van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy

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1318 Scopus citations

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

Original languageEnglish (US)
Pages (from-to)579-589
Number of pages11
JournalNature Genetics
Volume42
Issue number7
DOIs
StatePublished - Jul 2010

Bibliographical note

Funding Information:
We acknowledge funding from: the Academy of Finland (no. 124243); Agence Nationale de la Recherche (France); American Diabetes Association (1-05-RA-140, 7-08-MN-OK; 7-06-MN-05); Ardix Medical; Association Diabète Risque Vasculaire; Association de Langue Française pour l’Etude du Diabète et des Maladies Métaboliques; Association Française des Diabétiques; Bayer Diagnostics; British Diabetic Association Research; Becton Dickinson; Broad Institute of Harvard and Massachusetts Institute of Technology; The Burroughs Wellcome Fund; Cardionics; Center for Inherited Disease Research (USA); Centre for Medical Systems Biology (The Netherlands); Centre of Excellence Metabolic Disorders Baden-Wuerttemberg (Germany); Caisse Nationale Assurance Maladie des Travailleurs Salariés (France); Clinical Research Institute HUCH Ltd; Deutsche Forschungsgemeinschaft (DFG GrK 1041, DFG RA459, SFB 518); the Danish Diabetes Association; the Danish Health Research Council; Diabetes UK; Doris Duke Charitable Foundation; Erasmus Medical Center (The Netherlands); the Dutch Diabetes Foundation; European Community (HEALTH-F4-2007-201413, HEALTH-2007-B-223211, LSHG-CT-2006-01947, LSHM-CT-2004-512013, LSHM-CT-2004-005272, LSHM-CT-2006-518153); the European Foundation for the Study of Diabetes; the Federal Ministry of Health (Germany); the Federal Ministry of Education and Research (Germany) (FKZ01GS0823 and DZD e.V.); Fédération Française de Cardiologie; The Finnish Diabetes Research Foundation; The Folkhalsan Research Foundation; The Foundation for Strategic Research (Sweden); The Foundation of Bristol-Myers Squibb; the German National Genome Research Network; Helmholtz Zentrum München-Research Center for Environment and Health; INSERM (France); La Fondation de France; Lilly; The Linnaeus Centre for Bioinformatics (Sweden); the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care; the Medical Research Council UK (G0601261, G0000649; 081696); Munich Center of Health Sciences-LMU Innovativ (Germany); Merck Santé; the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano (Italy); the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (Germany); the Ministry of Science, Education and Sport (Croatia); the National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-25195, R01HL087641, R01HL59367, R01HL086694, N02-HL-6-4278); National Human Genome Research Institute (U01HG004402, U01HG004399, U01HG004171, 1 Z01 HG000024); the National Institute of Diabetes, Digestive and Kidney Diseases (DK078616, K24-DK080140, U54 DA021519, DK58845, DK069922, DK062370, DK073490, K23-DK65978 and DK072193); the US National Institutes of Health (HHSN268200625226C, HHSN268200625226C, 1K08AR055688, UL1RR025005, 1K99HL094535-01A1); the Netherlands Foundation for Scientific Research (175.010.2005.011, 047.017.043);

Funding Information:
Nord-Pas-de-Calais region (France); Novartis Pharma; Novo Nordisk; the Oxford National Institute for Health Research (NIHR) Biomedical Research Centre (UK); Office National Inter-professionnel des Vins; Peninsula Medical School, Exeter UK; Pfizer, Inc; Pierre Fabre laboratory (France); Programme National de Recherche sur le Diabète (France); Richard and Susan Family Foundation/American Diabetes Association Pinnacle Program Project; Roche; the Royal Society (UK); Russian Foundation for Basic Research (047.017.043); Sanofi-Aventis; Sarnoff Cardiovascular Research; Scottish Government Chief Scientist Office; SenterNovem (IOP Genomics grant IGE05012); Sigrid Juselius Foundation; the Skaraborg Institute, Skövde, Sweden; South Tyrolean Sparkasse Foundation; the Swedish Natural Sciences Research Council; The Swedish Research Council (349 2006-237P); the Association Diabète Risque Vasculaire (France); Topcon; the Wallenberg Foundation; and the Wellcome Trust (072960; 076113; 083270; 088885; 079557; 081682; 086596; 077016; 075491). A more complete list of acknowledgments is provided in the Supplementary Note.

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