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New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Nature Genetics 42, 105–116 (2010) | Download Citation

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  • An Erratum to this article was published on 01 May 2010

This article has been updated

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

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Change history

  • 26 March 2010

    In the version of this article initially published, there were several errors in the author affiliations. These errors have been corrected in the HTML and PDF versions of the article.

References

  1. 1.

    et al. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26, 3160–3167 (2003).

  2. 2.

    , , & The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 22, 233–240 (1999).

  3. 3.

    , , & Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care 25, 1845–1850 (2002).

  4. 4.

    UKPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837–853 (1998).

  5. 5.

    et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

  6. 6.

    , , , & 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).

  7. 7.

    et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 373, 1765–1772 (2009).

  8. 8.

    , & Type 2 diabetes: new genes, new understanding. Trends Genet. 24, 613–621 (2008).

  9. 9.

    Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: Where are the insulin resistance genes? Diabetologia 51, 1100–1110 (2008).

  10. 10.

    et al. A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses. Am. J. Hum. Genet. 79, 991–1001 (2006).

  11. 11.

    et al. The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes. Diabetologia 51, 70–75 (2008).

  12. 12.

    et al. A common missense variant in the glucokinase regulatory protein gene (GCKR) is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57, 3112–3121 (2008).

  13. 13.

    et al. A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 320, 1085–1088 (2008).

  14. 14.

    et al. Association studies in Caucasians identify variants in the G6PC2/ABCB11 region regulating fasting glucose levels. J. Clin. Invest. 118, 2620–2628 (2008).

  15. 15.

    et al. Variants in MTNR1B influence fasting glucose levels. Nat. Genet. 41, 77–81 (2009).

  16. 16.

    et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat. Genet. 41, 82–88 (2009).

  17. 17.

    et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat. Genet. 41, 89–94 (2009).

  18. 18.

    et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).

  19. 19.

    , , & Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

  20. 20.

    et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J. Clin. Endocrinol. Metab. 42, 222–229 (1976).

  21. 21.

    & Five stages of evolving β-cell dysfunction during progression to diabetes. Diabetes 53, S16–S21 (2004).

  22. 22.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  23. 23.

    & 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

  24. 24.

    et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat. Genet. 41, 35–46 (2009).

  25. 25.

    Diabetes Genetics Initiative of Broad Institute of Harvard and MIT. Lund University and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

  26. 26.

    , , & Replication validity of genetic association studies. Nat. Genet. 29, 306–309 (2001).

  27. 27.

    , , , & Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

  28. 28.

    et al. Normal fasting plasma glucose levels and type 2 diabetes in young men. N. Engl. J. Med. 353, 1454–1462 (2005).

  29. 29.

    et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat. Genet. advance online publication, doi:10.1038/ng.521 (17 January 2010).

  30. 30.

    et al. The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes 57, 2253–2257 (2008).

  31. 31.

    et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

  32. 32.

    et al. Eight blood pressure loci identified by genomewide association study of 34,433 people of European ancestry. Nat. Genet. 41, 666–676 (2009).

  33. 33.

    et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47–55 (2009).

  34. 34.

    et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009).

  35. 35.

    et al. Prediction of deleterious human alleles. Hum. Mol. Genet. 10, 591–597 (2001).

  36. 36.

    et al. Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res. 34, W645–W650 (2006).

  37. 37.

    et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 18, 4081–4088 (2009).

  38. 38.

    & Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

  39. 39.

    et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

  40. 40.

    et al. A survey of genetic human cortical gene expression. Nat. Genet. 39, 1494–1499 (2007).

  41. 41.

    et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

  42. 42.

    et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet. 4, e1000282 (2008).

  43. 43.

    et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum. Mol. Genet. 15, 1745–1756 (2006).

  44. 44.

    et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).

  45. 45.

    et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat. Genet. 41, 1110–1115 (2009).

  46. 46.

    , & The emerging genetic architecture of type 2 diabetes. Cell Metab. 8, 186–200 (2008).

  47. 47.

    et al. Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin. Diabetes 52, 2168–2174 (2003).

  48. 48.

    & Quantifying heterogeneity in a metaanalysis. Stat. Med. 21, 1539–1558 (2002).

  49. 49.

    , , & Glucose and carbachol generate 1,2-diacylglycerols by different mechanisms in pancreatic islets. J. Clin. Invest. 81, 1154–1161 (1988).

  50. 50.

    & Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol. Rev. 67, 1185–1248 (1987).

  51. 51.

    The role of gut hormones in glucose homeostasis. J. Clin. Invest. 117, 24–32 (2007).

  52. 52.

    et al. The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-β signaling pathways. PLoS One 3, e3642 (2008).

  53. 53.

    et al. The nuclear receptor LXR is a glucose sensor. Nature 445, 219–223 (2007).

  54. 54.

    et al. Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic β cells. Nature 349, 77–79 (1991).

  55. 55.

    & Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic β-cells. Biochem. Soc. Trans. 36, 955–958 (2008).

  56. 56.

    et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999).

  57. 57.

    et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004).

  58. 58.

    & Cross-talk between JIP3 and JIP1 during glucose deprivation: SEK1–JNK2 and Akt1 act as mediators. J. Biol. Chem. 280, 26845–26855 (2005).

  59. 59.

    et al. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat. Genet. 24, 291–295 (2000).

  60. 60.

    et al. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat. Genet. 17, 324–326 (1997).

  61. 61.

    et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat. Genet. 17, 327–330 (1997).

  62. 62.

    , , & GLIS3, a novel member of the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and activation functions. Nucleic Acids Res. 31, 5513–5525 (2003).

  63. 63.

    et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat. Genet. 38, 682–687 (2006).

  64. 64.

    , & A prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4α that regulates the cholesterol 7α-hydroxylase gene. J. Biol. Chem. 281, 10081–10088 (2006).

  65. 65.

    et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity- onset diabetes of the young (MODY1). Nature 384, 458–460 (1996).

  66. 66.

    , , & A novel gene family induced by acute inflammation in endothelial cells. Gene 342, 85–95 (2004).

  67. 67.

    Role of insulin-like growth factor in maintaining normal glucose homeostasis. Horm. Res. 62 (Suppl. 1), 77–82 (2004).

  68. 68.

    & Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007).

  69. 69.

    , , & GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

  70. 70.

    R Development Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, 2007).

  71. 71.

    Statistical methods in meta-analysis. in Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis (ed. Petitti, D.B.) 94–118 (Oxford University Press, New York, 2000).

  72. 72.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  73. 73.

    et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).

  74. 74.

    et al. Identification and purification of functional human β-cells by a new specific zinc-fluorescent probe. J. Histochem. Cytochem. 49, 519–528 (2001).

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Acknowledgements

A full list of Acknowledgments appears in the Supplementary Note.

Author information

    • Josée Dupuis
    • , Claudia Langenberg
    • , Inga Prokopenko
    • , Richa Saxena
    •  & Nicole Soranzo

    These authors contributed equally to this work.

Affiliations

  1. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Josée Dupuis
    •  & Alisa K Manning

  2. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Josée Dupuis
    •  & Caroline S Fox

  3. Medical Research Council (MRC), Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Claudia Langenberg
    • , Jian'an Luan
    • , Nita G Forouhi
    • , Manjinder Sandhu
    • , Stephen J Sharp
    • , Jing Hua Zhao
    • , Ruth J F Loos
    •  & Nicholas J Wareham

  4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Inga Prokopenko
    • , Anna L Gloyn
    • , Cecilia M Lindgren
    • , Reedik Mägi
    • , Amanda J Bennett
    • , Christopher J Groves
    • , Neelam Hassanali
    • , Paul R V Johnson
    • , Laura J McCulloch
    • , Matthew J Neville
    • , Nigel W Rayner
    • , Fredrik Karpe
    •  & Mark I McCarthy

  5. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Inga Prokopenko
    • , Cecilia M Lindgren
    • , Reedik Mägi
    • , Andrew P Morris
    • , Joshua Randall
    • , Anuj Goel
    • , John F Peden
    • , Nigel W Rayner
    • , Hugh Watkins
    • , Eleftheria Zeggini
    •  & Mark I McCarthy

  6. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Richa Saxena
    • , Benjamin F Voight
    • , Amanda Elliott
    • , Steven A McCarroll
    • , Gabe Crawford
    • , Jarred B McAteer
    • , David Altshuler
    •  & Jose C Florez

  7. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Richa Saxena
    • , Benjamin F Voight
    • , Amanda Elliott
    • , Steven A McCarroll
    • , David Altshuler
    •  & Jose C Florez

  8. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Nicole Soranzo
    • , Suzannah J Bumpstead
    • , Rhian Gwilliam
    • , Naomi Hammond
    • , Simon C Potter
    • , Dhiraj Varma
    • , Eleftheria Zeggini
    • , Panos Deloukas
    • , Timothy D Spector
    •  & Leena Peltonen

  9. Twin Research and Genetic Epidemiology Department, King's College London, St. Thomas' Hospital Campus, London, UK.

    • Nicole Soranzo
    • , Massimo Mangino
    • , Guangju Zhai
    •  & Timothy D Spector

  10. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Anne U Jackson
    • , Heather M Stringham
    • , Xijing Han
    • , Yun Li
    • , Laura J Scott
    • , Goncalo R Abecasis
    •  & Michael Boehnke

  11. Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Eleanor Wheeler
    • , Felicity Payne
    • , Rosa Maria Roccasecca
    •  & Inês Barroso

  12. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer

  13. Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8090, Pasteur Institute, Lille 2–Droit et Santé University, Lille, France.

    • Nabila Bouatia-Naji
    • , Christine Cavalcanti-Proença
    • , Amélie Bonnefond
    • , Jerome Delplanque
    • , Christian Dina
    • , Olivier Le Bacquer
    • , Cécile Lecoeur
    • , David Meyre
    •  & Philippe Froguel

  14. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Toby Johnson
    •  & Sven Bergmann

  15. University Institute of Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.

    • Toby Johnson
    •  & Murielle Bochud

  16. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Toby Johnson
    •  & Sven Bergmann

  17. Department of Epidemiology and Public Health, Imperial College London, Faculty of Medicine, Norfolk Place, London, UK.

    • Paul Elliott
    • , Lachlan J M Coin
    • , Ulla Sovio
    •  & Marjo-Riitta Jarvelin

  18. Boston University Data Coordinating Center, Boston, Massachusetts, USA.

    • Denis Rybin

  19. deCODE Genetics, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Valgerdur Steinthorsdottir
    • , G Bragi Walters
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson

  20. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

    • Peter Henneman

  21. Institute of Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.

    • Harald Grallert
    • , Christian Gieger
    • , Christa Meisinger
    • , Barbara Thorand
    • , H Erich Wichmann
    •  & Thomas Illig

  22. Department of Epidemiology, Erasmus Medical College, Rotterdam, The Netherlands.

    • Abbas Dehghan
    • , Albert Hofman
    • , Fernando Rivadeneira
    • , Eric J G Sijbrands
    • , André G Uitterlinden
    • , Jaqueline C M Witteman
    • , Cornelia M van Duijn
    •  & Yurii S Aulchenko

  23. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.

    • Jouke Jan Hottenga
    • , Eco J C de Geus
    • , Danielle Posthuma
    • , Gonneke Willemsen
    •  & Dorret I Boomsma

  24. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Christopher S Franklin
    • , Sarah H Wild
    • , Igor Rudan
    • , Harry Campbell
    •  & James F Wilson

  25. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK.

    • Pau Navarro
    • , Caroline Hayward
    • , Veronique Vitart
    •  & Alan F Wright

  26. Division of Genetics, Research and Development, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Kijoung Song
    • , Dawn M Waterworth
    •  & Vincent Mooser

  27. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

    • Anuj Goel
    • , John F Peden
    •  & Hugh Watkins

  28. Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • John R B Perry
    • , David Melzer
    • , Michael N Weedon
    •  & Timothy M Frayling

  29. National Institute of Aging, Baltimore, Maryland, USA.

    • Josephine M Egan

  30. Unit for Child and Adolescent Health and Welfare, National Institute for Health and Welfare, Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Taina Lajunen

  31. Hagedorn Research Institute, Gentofte, Denmark.

    • Niels Grarup
    • , Thomas Sparsø
    • , Torben Hansen
    •  & Oluf Pedersen

  32. Department of Medicine and Therapeutics, Level 7, Ninewells Hospital and Medical School, Dundee, UK.

    • Alex Doney

  33. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • Man Li
    •  & W H Linda Kao

  34. Department of Nutrition–Dietetics, Harokopio University, Athens, Greece.

    • Stavroula Kanoni
    •  & George V Dedoussis

  35. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Peter Shrader
    •  & James B Meigs

  36. Department of Epidemiology and Public Health, University College London, London, UK.

    • Meena Kumari
    • , Eric Brunner
    • , Aroon D Hingorani
    • , Mika Kivimaki
    •  & Michael Marmot

  37. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Lu Qi
    •  & Marilyn Cornelis

  38. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK.

    • Nicholas J Timpson
    • , Ian N M Day
    • , Debbie A Lawlor
    •  & George Davey Smith

  39. Fundación para la Investigación Biomédica del Hospital Clínico San Carlos, Madrid, Spain.

    • Carina Zabena
    • , María Teresa Martínez-Larrad
    •  & Manuel Serrano-Ríos

  40. Departments of Medicine and Human Genetics, McGill University, Montreal, Canada.

    • Ghislain Rocheleau
    •  & Robert Sladek

  41. Genome Quebec Innovation Centre, Montreal, Canada.

    • Ghislain Rocheleau
    •  & Robert Sladek

  42. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Erik Ingelsson
    • , Nancy L Pedersen
    •  & Patrik K E Magnusson

  43. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

    • Erik Ingelsson
    •  & Björn Zethelius

  44. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Ping An
    • , Michael A Province
    •  & Ingrid B Borecki

  45. 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

  46. INSERM U859, Universite de Lille-Nord de France, Lille, France.

    • François Pattou

  47. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.

    • Praveen Sethupathy
    • , Lori L Bonnycastle
    • , Peter Chines
    • , Michael R Erdos
    • , Mario A Morken
    • , Narisu Narisu
    • , Daniel Pearson
    • , Amy Swift
    • , Francis S Collins
    •  & David Schlessinger

  48. The Broad Institute, Cambridge, Massachusetts, USA.

    • Kristin Ardlie
    •  & Leena Peltonen

  49. Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.

    • Yavuz Ariyurek

  50. INSERM U780, Paris Sud University, Villejuif, France.

    • Beverley Balkau

  51. The Heart Research Institute, Sydney, New South Wales, Australia.

    • Philip Barter

  52. PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands West Australia, Australia.

    • John P Beilby
    •  & Jennie Hui

  53. School of Surgery and Pathology, University of Western Australia, Nedlands West Australia, Australia.

    • John P Beilby

  54. Department of Social Medicine, University of Bristol, Bristol, UK.

    • Yoav Ben-Shlomo

  55. Landspitali University Hospital, Reykjavik, Iceland.

    • Rafn Benediktsson
    •  & Gunnar Sigurðsson

  56. Icelandic Heart Association, Kopavogur, Iceland.

    • Rafn Benediktsson
    •  & Gunnar Sigurðsson

  57. The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle

  58. Steno Diabetes Center, Gentofte, Denmark.

    • Knut Borch-Johnsen

  59. Faculty of Health Science, University of Aarhus, Aarhus, Denmark.

    • Knut Borch-Johnsen
    •  & Oluf Pedersen

  60. Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Yvonne Böttcher
    • , Anke Tönjes
    •  & Michael Stumvoll

  61. Endocrinology–Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, France.

    • Guillaume Charpentier

  62. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Yii-Der Ida Chen
    • , Mark O Goodarzi
    •  & Jerome I Rotter

  63. Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK.

    • Robert Clarke

  64. Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Perth, Australia.

    • Matthew N Cooper
    • , Annette C Fedson
    • , Laila Simpson
    • , Kim L Ward
    •  & Lyle J Palmer

  65. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.

    • Laura Crisponi
    • , Silvia Naitza
    • , Marco Orrù
    • , Serena Sanna
    • , Antonio Cao
    • , Angelo Scuteri
    •  & Manuela Uda

  66. Western Australian Sleep Disorders Research Institute, Queen Elizabeth Medical Centre II, Perth, Australia.

    • Annette C Fedson
    • , David R Hillman
    • , Sutapa Mukherjee
    • , Laila Simpson
    • , Kim L Ward
    •  & Lyle J Palmer

  67. Department of Endocrinology, Diabetes and Nutrition, Charite-Universitaetsmedizin Berlin, Berlin, Germany.

    • Antje Fischer-Rosinsky
    • , Andreas F H Pfeiffer
    •  & Joachim Spranger

  68. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

    • Antje Fischer-Rosinsky
    • , Andreas F H Pfeiffer
    •  & Joachim Spranger

  69. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox
    •  & Gordon H Williams

  70. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

    • Rune Frants
    •  & Ko Willems van Dijk

  71. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.

    • Maria Grazia Franzosi

  72. Institut National de la Santé et de la Recherche Médicale, Institut National de la Recherche Agronomique, Université Paris 13, Bobigny Cedex, France.

    • Pilar Galan

  73. Department of Medicine III, Division Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.

    • Jürgen Graessler
    • , Stefan R Bornstein
    •  & Peter Schwarz

  74. Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Scott Grundy

  75. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

    • Ulf Gyllensten

  76. Centre Hospitalier Universitaire, de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0802, INSERM U927, Université de Poitiers, Unité de Formation et de Recherche, Médecine Pharmacie, Poitiers, France.

    • Samy Hadjadj

  77. Department of Public Health and Clinical Medicine, Section for Nutritional Research, Umeå University, Umeå, Sweden.

    • Göran Hallmans

  78. Department of Clinical Sciences, Obstetrics and Gynecology, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen

  79. Centre National de Génotypage/Institut de génomique/Commissariat á l'énergie atomique, Evry Cedex, France.

    • Simon C Heath
    • , G Mark Lathrop
    •  & Diana Zelenika

  80. INSERM U872, Faculté de Médecine Paris Descartes, Paris Cedex, France.

    • Serge Hercberg
    •  & Pierre Meneton

  81. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

    • Christian Herder
    •  & Michael Roden

  82. Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso, Bolzano, Italy, Affiliated Institute of the University Lübeck, Lübeck, Germany.

    • Andrew A Hicks
    • , Cristian Pattaro
    • , Irene Pichler
    •  & Peter Paul Pramstaller

  83. Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Perth, Australia.

    • David R Hillman
    •  & Sutapa Mukherjee

  84. Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia.

    • Jennie Hui
    •  & Lyle J Palmer

  85. Heart Institute of Western Australia, Sir Charles Gairdner Hospital, Nedlands West Australia, Australia.

    • Joe Hung

  86. School of Medicine and Pharmacology, University of Western Australia, Nedlands West Australia, Australia.

    • Joe Hung

  87. Folkhalsan Research Centre, Helsinki, Finland.

    • Bo Isomaa
    •  & Tiinamaija Tuomi

  88. Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland.

    • Bo Isomaa

  89. Nuffield Department of Surgery, University of Oxford, Oxford, UK.

    • Paul R V Johnson

  90. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.

    • Torben Jørgensen

  91. Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

    • Torben Jørgensen

  92. National Institute for Health and Welfare, Unit of Population Studies, Turku, Finland.

    • Antti Jula

  93. Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    •  & Marjo-Riitta Jarvelin

  94. Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
    •  & Jaakko Tuomilehto

  95. National Institute for Health and Welfare, Unit for Child and Adolescent Mental Health, Helsinki, Finland.

    • Jaakko Kaprio

  96. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
    • , Markus Perola
    • , Samuli Ripatti
    • , Peter J Wagner
    • , Kaisa Silander
    •  & Leena Peltonen

  97. Department of Internal Medicine and Biocenter Oulu, Oulu, Finland.

    • Y Antero Kesaniemi

  98. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • Beatrice Knight
    • , Beverley Shields
    •  & Andrew T Hattersley

  99. National Institute for Health and Welfare, Unit of Living Conditions, Health and Wellbeing, Helsinki, Finland.

    • Seppo Koskinen

  100. Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.

    • Peter Kovacs

  101. The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

    • Kirsten Ohm Kyvik

  102. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.

    • Valeriya Lyssenko
    •  & Leif Groop

  103. Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA.

    • Robert Mahley

  104. Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jarred B McAteer
    • , David M Nathan
    • , David Altshuler
    •  & Jose C Florez

  105. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jarred B McAteer
    • , David M Nathan
    • , Gordon H Williams
    • , David Altshuler
    • , James B Meigs
    •  & Jose C Florez

  106. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Ruth McPherson

  107. Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Matthew J Neville
    • , Fredrik Karpe
    •  & Mark I McCarthy

  108. Department of Clinical Genetics, Erasmus Medical College, Rotterdam, The Netherlands.

    • Ben A Oostra

  109. Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
    •  & Andrew D Morris

  110. Department of Geriatric Medicine and Metabolic Disease, Second University of Naples, Naples, Italy.

    • Giuseppe Paolisso

  111. National Institute for Health and Welfare, Unit of Public Health Genomics, Helsinki, Finland.

    • Markus Perola
    • , Samuli Ripatti
    • , Peter J Wagner
    • , Kaisa Silander
    •  & Leena Peltonen

  112. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

    • Markus Perola
    •  & Leena Peltonen

  113. Department of Medical Statistics, Epidemiology and Medical Informatics, Andrija Stampar School of Public Health, Medical School, University of Zagreb, Rockefellerova, Zagreb, Croatia.

    • Ozren Polasek

  114. Department of Clinical Genetics, VU University and Medical Center, Amsterdam, The Netherlands.

    • Danielle Posthuma

  115. Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland.

    • Anneli Pouta

  116. Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty

  117. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Bruce M Psaty

  118. Institute of Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

    • Wolfgang Rathmann

  119. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice

  120. Department of Internal Medicine, Erasmus Medical College, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    • , Eric J G Sijbrands
    • , André G Uitterlinden
    • , Mandy van Hoek
    •  & M Carola Zillikens

  121. Department of Metabolic Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

    • Michael Roden

  122. Department of Public Health and Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.

    • Olov Rolandsson

  123. School of Public Health, Department of General Practice, University of Aarhus, Aarhus, Denmark.

    • Annelli Sandbaek

  124. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Manjinder Sandhu

  125. MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK.

    • Avan Aihie Sayer
    • , Holly Syddall
    •  & Cyrus Cooper

  126. Department of Epidemiology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Paul Scheet

  127. Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany.

    • Udo Seedorf

  128. Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Angela Silveira

  129. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

    • Andrew Singleton

  130. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Nicholas L Smith

  131. Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith

  132. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Ann-Christine Syvänen
    •  & Lars Lind

  133. Medstar Research Institute, Baltimore, Maryland, USA.

    • Toshiko Tanaka

  134. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka

  135. Institut interrégional pour la santé (IRSA), La Riche, France.

    • Jean Tichet

  136. Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany.

    • Anke Tönjes

  137. Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

    • Tiinamaija Tuomi

  138. Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands.

    • Ko Willems van Dijk

  139. Research Unit, Cardiovascular Genetics, Nancy University Henri Poincaré, Nancy, France.

    • Sophie Visvikis-Siest

  140. EMGO Institute for Health and Care Research, Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.

    • Nicole Vogelzangs
    •  & Brenda W J H Penninx

  141. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Gérard Waeber
    •  & Peter Vollenweider

  142. Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.

    • Andrew Walley
    •  & Philippe Froguel

  143. Epidemiology and Public Health, Queen's University Belfast, Belfast, UK.

    • John W G Yarnell

  144. Medical Products Agency, Uppsala, Sweden.

    • Björn Zethelius

  145. National Institute for Health and Welfare, Unit of Chronic Disease Epidemiology and Prevention, Helsinki, Finland.

    • Veikko Salomaa

  146. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Frank B Hu

  147. Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Frank B Hu

  148. Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden.

    • Paul W Franks

  149. London School of Hygiene and Tropical Medicine, London, UK.

    • Shah Ebrahim

  150. Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • W H Linda Kao

  151. 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

  152. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • James S Pankow

  153. Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital National Health Service Trust, Norwich, UK.

    • Michael J Sampson

  154. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso

  155. Faculty of Health Science, University of Southern Denmark, Odense, Denmark.

    • Torben Hansen

  156. Institute of Biomedical Science, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

    • Oluf Pedersen

  157. Department of Neurology, General Central Hospital, Bolzano, Italy.

    • Peter Paul Pramstaller

  158. Department of Neurology, University of Lübeck, Lübeck, Germany.

    • Peter Paul Pramstaller

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

    • H Erich Wichmann

  160. Klinikum Grosshadern, Munich, Germany.

    • H Erich Wichmann

  161. School of Medicine, University of Split, Split, Croatia.

    • Igor Rudan

  162. Gen-Info Ltd., Zagreb, Croatia.

    • Igor Rudan

  163. 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

  164. Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Thomas A Buchanan

  165. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke

  166. National Institute for Health and Welfare, Unit of Diabetes Prevention, Helsinki, Finland.

    • Jaakko Tuomilehto
    •  & Timo T Valle

  167. South Ostrobothnia Central Hospital, Seinajoki, Finland.

    • Jaakko Tuomilehto

  168. Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA.

    • David S Siscovick

  169. Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.

    • Luigi Ferrucci

  170. Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson

  171. Lab of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

    • Angelo Scuteri

  172. Department of Clinical Sciences/Clinical Chemistry, University of Oulu, Oulu, Finland.

    • Aimo Ruokonen

  173. National Institute of Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Jarvelin

  174. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Richard M Watanabe

  175. MRC–Health Protection Agency Centre for Environment and Health, Imperial College London, London, UK.

    • Paul Elliott

Consortia

  1. DIAGRAM Consortium

    See Supplementary Note for a full list of authors.

  2. GIANT Consortium

    See Supplementary Note for a full list of authors.

  3. Global BPgen Consortium

    See Supplementary Note for a full list of authors.

  4. Anders Hamsten on behalf of Procardis Consortium

    1. Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet

  5. the MAGIC investigators

Authors

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Contributions

A full list of Author Contributions appears in the Supplementary Note.

Competing interests

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, Pfizer, 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.M., K.S. and D.M.W. are all full-time employees at GlaxoSmithKline. I.B. and spouse own stock in GlaxoSmithKline and Incyte.

Corresponding authors

Correspondence to Michael Boehnke or Mark I McCarthy or Jose C Florez or Inês Barroso.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 2–4 and Supplementary Figures 1–4

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    Supplementary Table 1

    Study characteristics for discovery (a) and replication (b) cohorts

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DOI

https://doi.org/10.1038/ng.520

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