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

A Corrigendum to this article was published on 29 March 2011

This article has been updated

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.

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Figure 1: Genome-wide Manhattan plots for the DIAGRAM+ stage 1 meta-analysis.
Figure 2: Regional plots of the 12 newly discovered T2D loci.
Figure 3: Plots of fasting blood glucose, insulin and derived indices for the established and new T2D loci.

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Change history

  • 27 August 2010

    In the version of this article initially published, there was an error in Table 1. Specifically, for rs5945326, the risk and non-risk alleles were reversed. The correct risk allele at rs5945326 is A, the non-risk allele is G and the risk allele frequency in HapMap CEU is 0.79. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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); 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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Manuscript writing: B.F.V., L.J.S., V.S., A.P.M., C.D., E.Z., T.F., T.M.F., R. Sladek, U.T., D.A., M.B., M.I.M.

Clinical samples: A.P.M., H.G., C.L., L.Q., M.v.H., P. Navarro, K.A., B. Balkau, R. Benediktsson, R. Blagieva, L.L.B., K.B.B., B. Bravenboer, N.P.B., G. Charpentier, M.C., A.S.F.D., C.S. Fox, C. Gieger, N.G., S.G., S.H., C. Herder, B.I., T.J., P.K., J.K., T.L., A.L., V.L., M.M., T.M., K.M., P. Nilsson, K.R.O., C. Platou, W.R., M.R., M.J.S., B.M.S., G.S., T.S., K. Strassburger, Q.S., B.T., J. Tichet, T.T., R.M.v.D., T.W.v.H., T.v.H., J.V.v.V.-O., C.W., R.N.B., F.S.C., U.G., T.H., G.A.H., D.J.H., K.H., M.Laakso, K.L.M., A.D.M., C.N.A.P., P.P.P., I.R., E.S., J. Tuomilehto, M.W., N.J.W., B.O.B., H.C., A.T.H., F.B.H., J.B.M., J.S.P., O.P., T.M.F., L.G., R. Sladek, U.T., H.-E.W., J.F.W., T.I., P.F., C.M.v.D., K. Stefansson, D.A., M.B., M.I.M.

Stage 1 genotyping and analysis: B.F.V., L.J.S., V.S., A.P.M., C.D., E.Z., C. Huth, Y.S.A., G.T., T.F., H.G., N.A., C.J.W., C.L., A.V.S., M.v.H., P. Navarro, K.A., R. Benediktsson, A.J.B., L.L.B., K.B.B., S.B., N.P.B., G. Charpentier, P.S.C., M.C., G. Crawford, M.R.E., M.G., N.G., C.J.G., C. Guiducci, C. Herder, B.I., A.U.J., N.K., T.L., C.M.L., V.L., M.M., T.M., M.A.M., N.N., P. Nilsson, F.P., G.R., R. Saxena, T.S., K. Strassburger, H.M.S., A.J.S., T.T., R.M.v.D., G.B.W., J.W., R.N.B., S.C., F.S.C., U.G., K.L.M., I.R., E.S., J. Tuomilehto, A.U., N.J.W., H.C., F.B.H., T.M.F., L.G., R. Sladek, U.T., H.-E.W., J.F.W., T.I., P.F., C.M.v.D., K. Stefansson, D.A., M.B., M.I.M.

Stage 2 genotyping and analysis: B.F.V., L.J.S., V.S., A.P.M., C.D., C. Huth, Y.S.A., G.T., H.G., N.A., C.J.W., C.L., J.D., L.Q., M.v.H., P. Navarro, K.A., A.J.B., E.B., L.L.B., K.B.B., S.B., N.P.B., P.S.C., M.C., D.J.C., G. Crawford, A.S.F.D., M.R.E., C.S. Franklin, M.G., C. Gieger, N.G., S.G., C.J.G., C. Guiducci, N.H., C. Herder, B.I., A.U.J., T.J., W.H.L.K., N.K., A.K., P.K., J.K., T.L., M. Li, C.M.L., V.L., T.M., K.M., M.A.M., N.N., P. Nilsson, F.P., A.-K.P., C. Proença, I.P., W.R., N.W.R., N.R.R., G.R., M.R., M.J.S., P.S., T.S., K. Strassburger, H.M.S., Q.S., A.J.S., T.T., R.M.v.D., T.W.v.H., J.V.v.V.-O., G.B.W., M.N.W., C.W., J.W., R.N.B., S.C., F.S.C., U.G., T.H., D.J.H., K.H., M. Laakso, K.L.M., A.D.M., C.N.A.P., P.P.P., I.R., E.S., J. Tuomilehto, A.U., N.J.W., H.C., M.J.D., F.B.H., J.S.P., O.P., I.B., J.C.F., T.M.F., L.G., R. Sladek, H.-E.W., U.T., J.F.W., T.I., P.F., C.M.v.D., D.A., M.B., M.I.M.

Analysis group: B.F.V., L.J.S., V.S., A.P.M., R.P.W., C.D., E.Z., C. Huth, Y.S.A., G.T., T.F., H.G., N.A., C.J.W., J.D., M.v.H., M.G., C. Gieger, A.U.J., N.K., A.K., J.R.B.P., A.-K.P., N.W.R., N.R.R., R. Saxena, M.J.D., P.F., M.B., M.I.M.

Biological analyses: V.S., G.T., L.J.M., S.A.M., J.D., K.S.E., A.L.E., P.R.V.J., V.L., I.P., A.L.G., J.B.M., U.T., K. Stefansson, M.I.M.

Informatics analyses: B.F.V., V.S., G.W., S.R., O.M.H., A.V.S., T.G., W.A.H., L.D.S.

DIAGRAM consortium management: B.F.V., L.J.S., V.S., A.P.M., C.D., E.Z., R.N.B., S.C., F.S.C., A.H., K.L.M., E.S., J. Tuomilehto, R.M.W., G.R.A., H.C., M.J.D., A.T.H., T.M.F., L.G., R. Sladek, U.T., H.-E.W., J.F.W., T.I., P.F., C.M.v.D., K. Stefansson, D.A., M.B., M.I.M.

Corresponding authors

Correspondence to James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke or Mark I McCarthy.

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Competing interests

V.S., G.T., G.B.W, A.K., U.T. and K.S. are employed by deCODE Genetics. R.M.W. has pharmaceutical funding. J.B.M. currently has research grants from GlaxoSmithKline and Sanofi-Aventis and serves on consultancy boards for Eli Lilly and Interleukin Genetics. J.C.F. has received consulting honoraria from Merck, bioStrategies, XOMA and Daiichi-Sankyo and has been a paid invited speaker at internal scientific seminars hosted by Pfizer and Alnylam Pharmaceuticals. R.M.W. has received consulting honoraria from Merck & Co. and Vivus Inc., currently has a grant from Merck & Co. and received research material support from Takeda Pharmaceuticals North America.

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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.

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Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1–6 (PDF 9274 kb)

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Voight, B., Scott, L., Steinthorsdottir, V. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42, 579–589 (2010). https://doi.org/10.1038/ng.609

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