Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Journal name:
Nature Genetics
Volume:
42,
Pages:
142–148
Year published:
DOI:
doi:10.1038/ng.521
Received
Accepted
Published online

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).

At a glance

Figures

  1. Regional plots of five genome-wide significant associations for 2 hour glucose based on 2 hour glucose discovery analysis adjusted for age, sex, BMI and study-specific covariates.
    Figure 1: Regional plots of five genome-wide significant associations for 2 hour glucose based on 2 hour glucose discovery analysis adjusted for age, sex, BMI and study-specific covariates.

    (ae) For each of the GCKR (a), ADCY5 (b), TCF7L2 (c), VPS13C (d) and GIPR (e) regions, directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36; hg 18). In each panel, the SNP taken forward for replication (large red diamond) and joint discovery and replication P value (blue diamond) are shown. Estimated recombination rates (HapMap) are plotted to reflect the local linkage disequilibrium structure around the associated SNPs and their correlated proxies (0 < r2 < 1, represented on a white to red scale, based on pairwise r2 values from HapMap CEU). Gene annotations were taken from the UCSC genome browser.

  2. Percent incretin effect in the Botnia, Denmark and EUGENE2-Kuopio studies of nondiabetic individuals (n = 804) by GIPR rs10423928 genotype.
    Figure 2: Percent incretin effect in the Botnia, Denmark and EUGENE2-Kuopio studies of nondiabetic individuals (n = 804) by GIPR rs10423928 genotype.

    Mean and s.d. for each study are displayed by genotype (see Supplementary Table 5 for details). Incretin effect was adjusted for age, sex and BMI and study-specific covariates.

  3. mRNA expression in human tissues of the genes located in the GIPR (a) and VPS13C (b) regions.
    Figure 3: mRNA expression in human tissues of the genes located in the GIPR (a) and VPS13C (b) regions.

    Expression data is relative expression levels measured by quantitative RT-PCR. All samples were run in triplicate and normalized to the GAPDH relative expression level. AU, arbitrary units.

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Author information

  1. These authors contributed equally to this work.

    • Richa Saxena &
    • Marie-France Hivert

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Richa Saxena,
    • Benjamin F Voight,
    • Gabriel J Crawford,
    • Jarred B McAteer,
    • David Altshuler &
    • Jose C Florez
  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Richa Saxena,
    • Benjamin F Voight,
    • Jarred B McAteer,
    • David Altshuler &
    • Jose C Florez
  3. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Marie-France Hivert,
    • Peter Shrader &
    • James B Meigs
  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Marie-France Hivert,
    • Gordon H Williams,
    • David M Nathan,
    • Jose C Florez &
    • James B Meigs
  5. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Claudia Langenberg,
    • Jian'an Luan,
    • Nita G Forouhi,
    • Stephen J Sharp,
    • Jing Hua Zhao,
    • Ruth J F Loos &
    • Nicholas J Wareham
  6. Medstar Research Institute, Baltimore, Maryland, USA.

    • Toshiko Tanaka
  7. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka &
    • Luigi Ferrucci
  8. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • James S Pankow
  9. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Peter Vollenweider,
    • Mathieu Firmann,
    • Vladimir Mayor &
    • Gérard Waeber
  10. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden.

    • Valeriya Lyssenko,
    • Jalal Taneera &
    • Leif Groop
  11. Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8090, Pasteur Institute, Lille 2-Droit et Santé University, Lille, France.

    • Nabila Bouatia-Naji,
    • Cécile Lecoeur,
    • Christian Dina,
    • Olivier Le Bacquer,
    • Amelie Bonnefond,
    • Christine Cavalcanti-Proença,
    • Jerome Delplanque,
    • David Meyre &
    • Philippe Froguel
  12. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Josée Dupuis &
    • Alisa K Manning
  13. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Anne U Jackson,
    • Heather M Stringham,
    • Laura J Scott &
    • Michael Boehnke
  14. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • W H Linda Kao,
    • Man Li &
    • Anna Köttgen
  15. Department of Medicine, School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • W H Linda Kao
  16. The Welch Center for Prevention, Epidemiology and Clinical Research, School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • W H Linda Kao
  17. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
  18. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Inga Prokopenko &
    • Mark I McCarthy
  19. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Inga Prokopenko &
    • Mark I McCarthy
  20. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Toby Johnson
  21. Hagedorn Research Institute, Gentofte, Denmark.

    • Niels Grarup,
    • Trine W Boesgaard,
    • Camilla H Andreasen,
    • Thomas Sparsø,
    • Torben Hansen &
    • Oluf Pedersen
  22. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Jeffrey O'Connell,
    • Braxton D Mitchell,
    • Ruth Pakyz &
    • Alan R Shuldiner
  23. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Erik Ingelsson
  24. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

    • Erik Ingelsson
  25. Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • David J Couper
  26. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice
  27. Genetics, Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Kijoung Song,
    • Dawn M Waterworth &
    • Vincent Mooser
  28. Institut National de la Santé et de la recherche médicale (INSERM), Universite de Lille-Nord de France, Lille, France.

    • François Pattou
  29. Centre Hospitalier Regional et Universitaire de Lille, Lille, France.

    • François Pattou
  30. deCODE Genetics, Reykjavik, Iceland.

    • Valgerdur Steinthorsdottir,
    • Gudmar Thorleifsson,
    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  31. Boston University Data Coordinating Center, Boston, Massachusetts, USA.

    • Denis Rybin
  32. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Kristin Ardlie
  33. Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital National Health Service Trust, Norwich, UK.

    • Michael Sampson
  34. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Lu Qi,
    • Marilyn Cornelis &
    • Frank B Hu
  35. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Mandy van Hoek
  36. Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • Michael N Weedon
  37. Department of Epidemiology and Biostatistics, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Yurii S Aulchenko
  38. Institute of Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany.

    • Harald Grallert,
    • Thomas Illig &
    • H Erich Wichmann
  39. INSERM, Villejuif, University Paris-Sud, Orsay, France.

    • Beverley Balkau
  40. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Richard N Bergman,
    • Thomas A Buchanan &
    • Richard M Watanabe
  41. Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • Suzette J Bielinski
  42. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.

    • Lori L Bonnycastle,
    • Peter S Chines,
    • Francis S Collins,
    • Michael R Erdos,
    • Mario A Morken,
    • Narisu Narisu,
    • Daniel Pearson &
    • Amy J Swift
  43. Steno Diabetes Center, Gentofte, Copenhagen, Denmark, and Faculty of Health Science, University of Aarhus, Aarhus, Denmark.

    • Knut Borch-Johnsen
  44. Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Yvonne Böttcher,
    • Anke Tönjes &
    • Michael Stumvoll
  45. Department of Epidemiology and Public Health, University College London, London, UK.

    • Eric Brunner,
    • Aroon Hingorani,
    • Mika Kivimaki,
    • Meena Kumari &
    • Michael Marmot
  46. Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Thomas A Buchanan
  47. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Suzannah J Bumpstead,
    • Felicity Payne,
    • Eleftheria Zeggini &
    • Inês Barroso
  48. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, France.

    • Guillaume Charpentier
  49. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Yii-Der Ida Chen,
    • Mark O Goodarzi &
    • Jerome I Rotter
  50. Department of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK.

    • Alex Doney
  51. Laboratory of Clinical Investigation, National Institute of Aging, Baltimore, Maryland, USA.

    • Josephine M Egan
  52. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox &
    • Gordon H Williams
  53. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Caroline S Fox
  54. Department of Medicine III, Division Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.

    • Jürgen Graessler,
    • Stefan R Bornstein &
    • Peter Schwarz
  55. Folkhalsan Research Centre, Helsinki, Finland.

    • Bo Isomaa &
    • Tiinamaija Tuomi
  56. Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland.

    • Bo Isomaa
  57. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.

    • Torben Jørgensen
  58. Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

    • Torben Jørgensen
  59. Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.

    • Peter Kovacs &
    • Knut Krohn
  60. Department of General Practice, University of Aarhus, Aarhus, Denmark.

    • Torsten Lauritzen &
    • Annelli Sandbaek
  61. INSERM, Robert Debre Hospital, Paris, France.

    • Claire Lévy-Marchal
  62. Paris Diderot University, Paris, France.

    • Claire Lévy-Marchal
  63. Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jarred B McAteer,
    • David M Nathan &
    • Jose C Florez
  64. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke
  65. Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer &
    • Andrew D Morris
  66. Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle upon Tyne, UK.

    • Laura Pascoe &
    • Mark Walker
  67. Institute of Biometrics and Epidemiology, German Diabetes Centre, Duesseldorf, Germany.

    • Wolfgang Rathmann
  68. MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK.

    • Avan Aihie Sayer,
    • Holly Syddall &
    • Cyrus Cooper
  69. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Eric Sijbrands &
    • Cornelia van Duijn
  70. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

    • Andrew Singleton
  71. Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA.

    • David S Siscovick
  72. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Nicholas L Smith
  73. Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith
  74. Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany.

    • Anke Tönjes
  75. Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

    • Tiinamaija Tuomi &
    • Jaakko Tuomilehto
  76. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland.

    • Jaakko Tuomilehto
  77. Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland.

    • Timo T Valle
  78. Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.

    • Andrew Walley &
    • Philippe Froguel
  79. Full membership list of the GIANT consortium is provided in the Supplementary Note.

  80. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H Erich Wichmann
  81. Klinikum Grosshadern, Munich, Germany.

    • H Erich Wichmann
  82. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, UK.

    • James F Wilson
  83. Channing Laboratory, Brigham and Women′s Hospital and Harvard Medical School Boston, Massachusetts, USA.

    • Frank B Hu
  84. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.

    • Timothy M Frayling &
    • Andrew T Hattersley
  85. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.

    • Timothy M Frayling &
    • Andrew T Hattersley
  86. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  87. Department of Clinical Sciences, Medicine, Lund University, University Hospital Malmo, Malmo, Sweden.

    • Peter Nilsson
  88. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Ann-Christine Syvänen
  89. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  90. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto &
    • Markku Laakso
  91. Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  92. The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle
  93. Faculty of Health Science, University of Southern Denmark, Odense, Denmark.

    • Torben Hansen
  94. Institute of Biomedicine, Faculty of Health Science, University of Copenhagen and Faculty of Health Science, University of Aarhus, Denmark.

    • Oluf Pedersen
  95. Oxford National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  96. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

    • Robert Sladek
  97. Genome Quebec Innovation Centre, Montreal, Quebec, Canada.

    • Robert Sladek
  98. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Richard M Watanabe

Consortia

  1. GIANT consortium

  2. the MAGIC investigators

    • Thomas Illig,
    • H Erich Wichmann,
    • James F Wilson,
    • Cornelia van Duijn,
    • Frank B Hu,
    • Andrew D Morris,
    • Timothy M Frayling,
    • Andrew T Hattersley,
    • Unnur Thorsteinsdottir,
    • Kari Stefansson,
    • Peter Nilsson,
    • Ann-Christine Syvänen,
    • Alan R Shuldiner,
    • Mark Walker,
    • Stefan R Bornstein,
    • Peter Schwarz,
    • Gordon H Williams,
    • David M Nathan,
    • Johanna Kuusisto,
    • Markku Laakso,
    • Cyrus Cooper,
    • Michael Marmot,
    • Luigi Ferrucci,
    • Vincent Mooser,
    • Michael Stumvoll,
    • Ruth J F Loos,
    • David Altshuler,
    • Bruce M Psaty,
    • Jerome I Rotter,
    • Eric Boerwinkle,
    • Torben Hansen,
    • Oluf Pedersen,
    • Jose C Florez,
    • Mark I McCarthy,
    • Michael Boehnke,
    • Inês Barroso,
    • Robert Sladek,
    • Philippe Froguel,
    • James B Meigs,
    • Leif Groop,
    • Nicholas J Wareham &
    • Richard M Watanabe

Contributions

Writing group: R. Saxena, M.-F.H., C. Langenberg., T. Tanaka, J.S.P., P.V., V.L., N.B.-N., J.C.F., M.I.M., M.B., I.B., R. Sladek, P.F., J.B.M., L.G., N.J.W., R.M.W.

Project design, management and coordination: (Amish) B.D.M., A.R.S.; (ARIC) J.S.P., W.H.L.K., S.J. Bielinski, E. Boerwinkle; (BLSA) A. Singleton, L.F.; (BotniaPPP) L.G., T. Tuomi., B.I.; (CHS) N.L.G., K.R., N.L.S., B.M.P., J.I.R.; (Colaus) P.V., M.F., V. Mayor, G.W., D.M.W., V. Mooser; (Danish) K.B.J., A.S., T. Jørgensen, T.L., T.H., O.P.; (DIAGEN) P. Schwartz, S.R.B.; (DGI) R. Saxena, D.A., L.G.; (Ely) C. Langenberg, N.J.W.; (Fenland) C. Langenberg, N.G.F., R.J.F.L., N.J.W.; (FHS) J.D., J.B.M.; (French) N.B.-N., P.F.; (FUSION) R.N.B., F.S.C., K.L.M., L.J.S., J. Tuomilehto, M.B., R.M.W.; (Hertfordshire) A.A.S., H.S., C.C.; (METSIM) J.K., M.La.; (MPP) P.N.; (Partners/Roche) J.B.M., D.M.N., G.H.W.; (RISC) M.W., L.P.; (Sorbs) A.T., M.S.; (ULSAM) E.I.; (Whitehall II) E. Brunner, A.H., M. Kivimaki, M. Kumari, M.M.

Sample collection and phenotyping: (Amish) A.R.S.; (BLSA) J.M.E.; (BotniaPPP) L.G., V.L., B.I., T. Tuomi; (CHS) B.M.P., D.S.S, N.L.S.; (CoLaus) P.V., G.W.; (Danish) T.W.B., K.B.J, A.S., T. Jørgensen, T.L., T.H., O.P.; (DIAGEN) J.G., P. Schwartz; (DGI) L.G., V.L., B.I., T. Tuomi; (Ely) N.J.W.; (Fenland) N.G.F., R.J.F.L., N.J.W.; (French) P.F., D.M., B.B., C.L.-M., G.C., F. Pattou; (FHS) J.B.M., C.S.F.; (FUSION) R.N.B., T.A.B., J. Tuomilehto, T.T.V.; (Hertfordshire) A.A.S., H.S., C.C.; (METSIM) J.K., M. Laakso; (Partners/Roche) J.B.M., D.M.N., G.H.W.; (Sorbs) P.K., A.T.; (Whitehall II) E. Brunner, M. Kumari, M.M.

Genotyping: (Amish) R.P.; (ARIC) E. Boerwinkle.; (BLSA) A. Singleton; (BotniaPPP) G.J.C.; (CHS) Y.-D.I.C., M.O.G., J.I.R.; (CoLaus) V. Mooser, D.M.W.; (Danish) T.H., T.S., C.H.A., N.G., O.P.; (DGI) D.A., V.L., R. Saxena; (DIAGEN) D.P., A.J.S.; (Ely) I.B., S.J. Bumpstead, F. Payne, N.J.W.; (Fenland) R.J.F.L., N.J.W.; (FHS) J.C.F., J.B.M.; (French) N.B.-N., J.D., R. Sladek, D.M., A.W.; (FUSION) L.L.B., M.R.E., P.S.C.; (FUSION stage 2) P.S.C., A.J.S.; (Hertfordshire) I.B., S.J. Bumpstead, F. Payne, N.J.W.; (METSIM) M.A.M., N.N.; (Partners/Roche) J.C.F., J.B.M.; (Sorbs) Y.B., P.K., K.K.; (ULSAM) A.-C.S.; (Whitehall II) M. Kumari, C. Langenberg, N.J.W.

Statistical analysis: (Meta-analyses) R. Saxena, J.D., D.R., W.H.L.K., A.U.J.; (Amish) J.O.; (ARIC) W.H.L.K., M.L., A.K., D.J.C.; (BLSA) T. Tanaka; (BotniaPPP) V.L.; (CHS) N.L.G., K.R.; (CoLaus) T. Johnson, K. Song; (Danish) T.S., C.H.A., T.W.B., N.G.; (DGI) R. Saxena; (Ely) C. Langenberg, S.J.S.; (Fenland) C. Langenberg, J.L., J.H.Z.; (French) N.-B.N, C. Lecoeur, C.C-P., A.B., C.D.; (FHS) J.D., A.K.M., D.R., P. Shrader; (FUSION) A.U.J., H.M.S.; (FUSION stage 2) A.U.J., H.M.S.; (Hertfordshire) C. Langenberg, S.J.S.; (Partners/Roche) P.Shr.; (RISC) C. Langenberg, S.J.S.; (Sorbs) I.P.; (ULSAM) E.I.; (Whitehall II) C. Langenberg.

Expression analysis: (Malmo) J. Taneera, V.L., L.G; (French) N.B.-N., O.L.B., F. Patou, P.F.

Type 2 Diabetes association: (DGI) D.A., L.G., R. Saxena, B.F.V., K.A.; (deCODE) V.S., G.T., U.T., K. Stefansson; (EUROSPAN) Y.S.A., J.F.W., M.v.H., E.S., C.v.D.; (French) N.B.-N., J. Deplanque, C. Lecoeur, G.C., P.F.; (Addition-Ely) C. Langenberg, F. Payne, S.J. Bumpstead, I.B., N.J.W.; (Norfolk Diabetes Case-Control Study) C. Langenberg, F. Payne, S.J. Bumpstead, I.B., M.S., N.J.W.; (Cambridgeshire Case-Control Study) C. Langenberg, F. Payne, S.J. Bumpstead, I.B., N.J.W.; (KORA) H.G., W.R., T.I., H.E.W.; (MPP) P.N., V.L., L.G.; (NHS/HPFS) F.B.H. L.Q., M.C.C.; (UKT2D/58BC/OXGN) A.D., C.N.A.P., A.T.H., A.D.M.; T.M.F., M.I.M.; (WTCCC-UKT2D) M.N.W., E.Z.

Richa Saxena1,2,99, Marie-France Hivert3,4,99, Claudia Langenberg5, Toshiko Tanaka6,7, James S Pankow8, Peter Vollenweider9, Valeriya Lyssenko10, Nabila Bouatia-Naji11, Josée Dupuis12, Anne U Jackson13, W H Linda Kao14,15,16, Man Li14, Nicole L Glazer17, Alisa K Manning12, Jian'an Luan5, Heather M Stringham13, Inga Prokopenko18,19, Toby Johnson20, Niels Grarup21, Trine W Boesgaard21, Cécile Lecoeur11, Peter Shrader3, Jeffrey O'Connell22, Erik Ingelsson23,24, David J Couper25, Kenneth Rice26, Kijoung Song27, Camilla H Andreasen21, Christian Dina11, Anna Köttgen14, Olivier Le Bacquer11, François Pattou28,29, Jalal Taneera10, Valgerdur Steinthorsdottir30, Denis Rybin31, Kristin Ardlie32, Michael Sampson33, Lu Qi34, Mandy van Hoek35, Michael N Weedon36, Yurii S Aulchenko37, Benjamin F Voight1,2, Harald Grallert38, Beverley Balkau39, Richard N Bergman40, Suzette J Bielinski41, Amelie Bonnefond11, Lori L Bonnycastle42, Knut Borch-Johnsen43, Yvonne Böttcher44, Eric Brunner45, Thomas A Buchanan40,46, Suzannah J Bumpstead47, Christine Cavalcanti-Proença11, Guillaume Charpentier48, Yii-Der Ida Chen49, Peter S Chines42, Francis S Collins42, Marilyn Cornelis34, Gabriel J Crawford1, Jerome Delplanque11, Alex Doney50, Josephine M Egan51, Michael R Erdos42, Mathieu Firmann9, Nita G Forouhi5, Caroline S Fox52,53, Mark O Goodarzi49, Jürgen Graessler54, Aroon Hingorani45, Bo Isomaa55,56, Torben Jørgensen57,58, Mika Kivimaki45, Peter Kovacs59, Knut Krohn59, Meena Kumari45, Torsten Lauritzen60, Claire Lévy-Marchal61,62, Vladimir Mayor9, Jarred B McAteer1,2,63, David Meyre11, Braxton D Mitchell22, Karen L Mohlke64, Mario A Morken42, Narisu Narisu42, Colin N A Palmer65, Ruth Pakyz22, Laura Pascoe66, Felicity Payne47, Daniel Pearson42, Wolfgang Rathmann67, Annelli Sandbaek60, Avan Aihie Sayer68, Laura J Scott13, Stephen J Sharp5, Eric Sijbrands69, Andrew Singleton70, David S Siscovick71, Nicholas L Smith72,73, Thomas Sparsø21, Amy J Swift42, Holly Syddall68, Gudmar Thorleifsson30, Anke Tönjes44,74, Tiinamaija Tuomi55,75, Jaakko Tuomilehto75,76, Timo T Valle77, Gérard Waeber9, Andrew Walley78, Dawn M Waterworth27, Eleftheria Zeggini47, Jing Hua Zhao5, GIANT consortium79, Thomas Illig38, H Erich Wichmann38,80,81, James F Wilson82, Cornelia van Duijn69, Frank B Hu34,83, Andrew D Morris65, Timothy M Frayling84,85, Andrew T Hattersley84,85, Unnur Thorsteinsdottir30,86, Kari Stefansson30,86, Peter Nilsson87, Ann-Christine Syvänen88, Alan R Shuldiner22,89, Mark Walker66, Stefan R Bornstein54, Peter Schwarz54, Gordon H Williams4,52, David M Nathan4,63, Johanna Kuusisto90, Markku Laakso90, Cyrus Cooper68, Michael Marmot45, Luigi Ferrucci7, Vincent Mooser27, Michael Stumvoll44, Ruth J F Loos5, David Altshuler1,2, Bruce M Psaty91, Jerome I Rotter49, Eric Boerwinkle92, Torben Hansen21,93, Oluf Pedersen21,94, Jose C Florez1,2,4,63, Mark I McCarthy18,19,95, Michael Boehnke13, Inês Barroso47, Robert Sladek96,97, Philippe Froguel11,78, James B Meigs3,4, Leif Groop10, Nicholas J Wareham5 & Richard M Watanabe40,98 for the MAGIC investigators

Competing financial interests

J.B.M. currently has research grants from GlaxoSmithKline and Sanofi-aventis, and serves on consultancy boards for GlaxoSmithKline, Sanofi-aventis, Interleukin Genetics, Kalypsis, and Outcomes Sciences. J.C.F. has received consulting honoraria from Merck, bioStrategies, XOMA and Publicis Healthcare Communications Group, a global advertising agency engaged by Amylin Pharmaceuticals. deCODE authors are employees at deCODE genetics and own stock or stock options in the company. P.W.F. has received consulting honoraria from Unilever. P.V. and G.W. received financial support from GlaxoSmithKline to build the CoLaus study. V.Mo., K.S. and D.M.W. are all full-time employees at GlaxoSmithKline. I.B. and spouse own stock in GlaxoSmithKline and Incyte. A.S. has research support from GlaxoSmithKline. 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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Supplementary information

PDF files

  1. Supplementary Text and Figures (976K)

    Supplementary Figure 1, Supplementary Tables 2–6 and Supplementary Note

Excel files

  1. Supplementary Table 1 (84K)

    Cohort and study characteristics and details of analysis metrics and methods

  2. Supplementary Table 2 (60K)

    Meta-analysis of association results for 2-hr glucose across discovery and replication cohorts

  3. Supplementary Table 4 (48K)

    Association of rs10423928 [GIPR], rs17271305 [VPS13C] and rs2877716 [ADCY5] with insulinogenic index, AUC (area under the curve) insulin/glucose, and 2h insulin (adjusted for 2h glucose) within MAGIC and meta-analysis across all studies

Additional data