Article | Published:

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Nature Genetics volume 47, pages 14151425 (2015) | Download Citation

Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

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References

  1. 1.

    et al. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat. Genet. 43, 984–989 (2011).

  2. 2.

    et al. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in East Asians. Nat. Genet. 44, 67–72 (2012).

  3. 3.

    et al. Twelve type 2 diabetes susceptibility loci identified through large scale association analysis. Nat. Genet. 42, 579–589 (2010).

  4. 4.

    et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).

  5. 5.

    et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat. Genet. 46, 234–244 (2014).

  6. 6.

    et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).

  7. 7.

    et al. Large-scale association studies of variants in genes encoding the pancreatic-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) conrm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52, 568–572 (2003).

  8. 8.

    et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

  9. 9.

    et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes. Nat. Genet. 42, 105–116 (2010).

  10. 10.

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  11. 11.

    et al. Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture? Am. J. Hum. Genet. 91, 466–477 (2012).

  12. 12.

    et al. Chromatin marks identify critical cell types for fine-mapping complex trait variants. Nat. Genet. 45, 124–130 (2013).

  13. 13.

    et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbour human disease risk variants. Proc. Natl. Acad. Sci. USA 110, 17921–17926 (2013).

  14. 14.

    et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014).

  15. 15.

    et al. The Metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 8, e1002793 (2012).

  16. 16.

    International HapMap Project Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  17. 17.

    1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  18. 18.

    1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  19. 19.

    & Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

  20. 20.

    et al. Quality control and conduct of genome-wide association meta-analyses. Nat. Protoc. 9, 1192–1212 (2014).

  21. 21.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  22. 22.

    , , , & Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

  23. 23.

    et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).

  24. 24.

    et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat. Genet. 40, 1098–1102 (2008).

  25. 25.

    , & Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1. Nat. Genet. 32, 426–431 (2002).

  26. 26.

    et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

  27. 27.

    et al. Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction. Nat. Genet. 43, 801–805 (2011).

  28. 28.

    et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).

  29. 29.

    et al. A role for coding functional variants in HNF4A in type 2 diabetes susceptibility. Diabetologia 54, 111–119 (2011).

  30. 30.

    et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

  31. 31.

    et al. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene. Diabetes 53, 1360–1368 (2004).

  32. 32.

    et al. Co-expression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K+ channel. Diabetes 58, 2419–2424 (2009).

  33. 33.

    et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes–associated variants. Diabetes 58, 2070–2083 (2009).

  34. 34.

    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).

  35. 35.

    et al. Common variants in HNF-1α and risk of type 2 diabetes. Diabetologia 49, 2882–2891 (2006).

  36. 36.

    et al. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458 (1996).

  37. 37.

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

  38. 38.

    et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014).

  39. 39.

    et al. Species-specific strategies underlying conserved functions of metabolic transcription factors. Mol. Endocrinol. 25, 694–706 (2011).

  40. 40.

    et al. A map of open chromatin in human pancreatic islets. Nat. Genet. 42, 255–259 (2010).

  41. 41.

    , , , & Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus. PLoS Genet. 10, e1004633 (2014).

  42. 42.

    et al. A genome-wide approach accounting for body-mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat. Genet. 44, 659–669 (2012).

  43. 43.

    et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes 63, 2158–2171 (2014).

  44. 44.

    et al. A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J. Clin. Invest. 121, 3589–3597 (2011).

  45. 45.

    et al. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc. Natl. Acad. Sci. USA 111, 13924–13929 (2014).

  46. 46.

    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).

  47. 47.

    et al. Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β-cell. Mol. Endocrinol. 24, 1594–1604 (2010).

  48. 48.

    et al. TCF7L2 is a master regulator of insulin production and processing. Hum. Mol. Genet. 23, 6419–6431 (2014).

  49. 49.

    et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J. Clin. Invest. 117, 2155–2163 (2007).

  50. 50.

    et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med. 350, 1838–1849 (2004).

  51. 51.

    et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 46, 357–363 (2014).

  52. 52.

    , , , & Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010).

  53. 53.

    et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat. Genet. 44, 297–301 (2012).

  54. 54.

    & Pioneer transcription factors: establishing a competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

  55. 55.

    et al. Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 22, 3435–3448 (2008).

  56. 56.

    , , & The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).

  57. 57.

    et al. Large-scale association analyses identify new loci influencing glycaemic traits and provide insight into the underlying biological pathways. Nat. Genet. 44, 991–1005 (2012).

  58. 58.

    , , , & Genetic variants of FOXA2: risk of type 2 diabetes and effect on metabolic traits in North Indians. J. Hum. Genet. 53, 957–965 (2008).

  59. 59.

    , , , & Genome-wide analyses of ChIP-Seq derived FOXA2 DNA occupancy in liver points to genetic networks underpinning multiple complex traits. J. Clin. Endocrinol. Metab. 99, E1580–E1585 (2014).

  60. 60.

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

  61. 61.

    Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am. J. Hum. Genet. 81, 208–227 (2007).

  62. 62.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  63. 63.

    et al. The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

  64. 64.

    , & Design and analysis of ChIP-seq experiments for DNA-binding proteins. Nat. Biotechnol. 26, 1351–1359 (2008).

  65. 65.

    , , & Measuring reproducibility of high-throughput experiments. Ann. App. Stat. 5, 1752–1779 (2011).

  66. 66.

    et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell 143, 156–169 (2010).

  67. 67.

    & Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat. Biotechnol. 28, 817–825 (2010).

  68. 68.

    et al. Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. 16, 435–448 (2012).

  69. 69.

    & BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

  70. 70.

    & MEME-ChiP. Motif analysis of large DNA datasets. Bioinformatics 27, 1696–1697 (2011).

  71. 71.

    et al. JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles. Nucleic Acids Res. 42, D142–D147 (2014).

  72. 72.

    et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B-cell identifies. Mol. Cell 38, 576–589 (2010).

  73. 73.

    et al. MEME Suite: tools for motif discovery and searching. Nucleic Acids Res. 37, W202–W208 (2009).

  74. 74.

    , & FIMO: scanning for occurrences of a given motif. Bioinformatics 27, 1017–1018 (2011).

  75. 75.

    , , & Functional analysis of an oxygen-regulated transcriptional enhancer lying 3′ to the mouse erythropoietin gene. Proc. Natl. Acad. Sci. USA 88, 10553–10557 (1991).

Download references

Acknowledgements

Funding for the research undertaken in this study has been received from the Academy of Finland (including grants 77299, 102318, 10493, 118065, 123885, 124243, 129293, 129680, 136895, 139635, 211119, 213506, 251217 and 263836); Agence National de la Recherche; Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques; Association Diabèete Risque Vasculaire; Association Française des Diabétiques; the Association of Danish Pharmacies; the Augustinus Foundation; the Becket Foundation; the British Diabetes Association (BDA) Research; the British Heart Foundation; the Central Norway Health Authority; the Central Finland Hospital District; the Center for Inherited Disease Research (CIDR); the City of Kuopio; the City of Leutkirch; Copenhagen County; the Danish Centre for Evaluation and Health Technology Assessment; the Danish Council for Independent Research; the Danish Heart Foundation; the Danish Research Councils; Deutsche Forschungsgemeinschaft (including project ER 155/6-2); the Diabetes Research Foundation; Diabetes UK; the Doris Duke Charitable Foundation; Erasmus Medical Center; Erasmus University; the Estonian government (SF0180142s08); the European Commission (including ENGAGE HEALTH-F4-2007-201413, FP7-201413, FP7-245536, EXGENESIS LSHM-CT-2004-005272, FP6 LSHM_CT_2006_037197, LSHM-CT-2007-037273, Directorate C-Public Health 2004310, DG XII); the European Regional Development Fund; the Federal Ministry of Education and Research, Germany (including FKZ 01GI1128 and FKZ 01EO1001); the Federal Ministry of Health, Germany; the Finnish Diabetes Association; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Medical Society; the Folkhalsan Research Foundation; the Foundation for Life and Health in Finland; the Foundation for Old Servants; the Fredrick och Ingrid Thuring Foundation; the French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Région); the German Center for Diabetes Research; the German Research Council (including grant GRK1041); the German National Genome Research Network; Groupe d'Etude des Maladies Métaboliques et Systémiques; the Health Care Centers in Vasa, Närpes and Korsholm, Finland; the Health Foundation; the Heinz Nixdorf Foundation; Helmholtz Zentrum München; the Helsinki University Central Hospital Research Foundation; the Hospital District of Southwest Finland; the Ib Henriksens Foundation; IngaBritt and Arne Lundberg's Research Foundation (including grant 359); Karolinska Institutet; the Knut and Alice Wallenberg Foundation (including grant KAW 2009.0243); Kuopio University Hospital; the Lundbeck Foundation; the Magnus Bergvall Foundation; the Medical Faculty of University Duisburg-Essen; the Medical Research Council, UK (including grants G0000649 and G0601261); the Ministry for Health, Welfare and Sports, the Netherlands; the Ministry of Education and Culture, Finland (including grants 722 and 627; 2004-2011); the Ministry of Education, Culture and Science, the Netherlands; the Ministry of Health and Prevention, Denmark; the Ministry of Social Affairs and Health, Finland; the Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany; the Munich Center of Health Sciences; the Municipal Health Care Center and Hospital in Jakobstad, Finland; the municipality of Rotterdam, the Netherlands; the Närpes Health Care Foundation; the National Health Screening Service of Norway; the National Heart, Lung, and Blood Institute, USA (including grant numbers/contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01HC25195, N02HL64278, R01HL087641, R01HL59367 and R01HL086694); the National Human Genome Research Institute, USA (including grant numbers/contracts U01HG004402 and N01HG65403); the National Institute for Diabetes and Digestive and Kidney Diseases, USA (including grants R01DK078616, U01DK085526, K24DK080140 and R01DK073490); the National Institute for Health and Welfare, Finland; the National Institutes of Health, USA (including grant numbers/contracts HHSN268200625226C, UL1RR025005, R01DK062370, R01DK072193, 1Z01HG000024, AG028555, AG08724, AG04563, AG10175, AG08861, U01HG004399, DK58845, CA055075, DK085545 and DK098032); the Netherlands Genomics Initiative; the Netherlands Organisation for Health Research and Development; the Netherlands Organisation of Scientific Research NOW Investments (including grants 175.010.2005.011, 911-03-012 and 050-060-810); the Nord-Trondelag County Council; the Nordic Center of Excellence in Disease Genetics; the Norwegian Institute of Public Health; the Norwegian Research Council; the Novo Nordisk Foundation; the Ollquist Foundation; the Oxford National Institute for Health Research (NIHR) Biomedical Research Centre; the Paavo Nurmi Foundation; the Paivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Pirkanmaa Hospital District, Finland; Programme Hospitalier de Recherche Clinique; Programme National de Recherche sur la Diabète; the Research Institute for Diseases in the Elderly (including grant 014-93-015); the Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center; the Royal Swedish Academy of Sciences; Sarstedt, Germany; the Signe and Ane Gyllenberg Foundation; the Sigrid Juselius Foundation; the Slottery Machine Association, Finland; the Social Insurance Institution of Finland; the South OstroBothnia Hospital District; the state of Baden-Württemberg, Germany; the Stockholm County Council (including grant 560183); the Swedish Cultural Foundation, Finland; the Swedish Diabetes Foundation; the Swedish e-science Research Center; the Swedish Foundation for Strategic Research; the Swedish Heart-Lung Foundation; the Swedish Research Council (including grants SFO EXODIAB 2009-1039, 521-2010-3490, 521-2007-4037, 521-2008-2974, ANDIS 825-2010-5983, LUDC 349-2008-6589 and 8691); the Swedish Society of Medicine; the Tore Nilsson Foundation; the Torsten and Ragnar Soderbergs Stiftelser (including grant MT33/09); University Hospital Essen; University of Tromsø; the University College London NIHR Biomedical Research Centre; the UK NIHR Cambridge Biomedical Research Centre; Uppsala University; Uppsala University Hospital; the Vaasa Hospital District; the Velux Foundation; and the Wellcome Trust (including the Biomedical Collections Grant GR072960 and grants 076113, 083948, 090367, 090532, 083270, 086596, 098017, 095101, 098051 and 098381). We are grateful to R. Scharfmann (INSERM U1016, Cochin Institute Paris) for the gift of EndoC βH1 cells and for providing technical support with their maintenance. We thank P. Johnson and the Oxford NIHR Biomedical Research Centre–funded Islet Isolation facility for providing human islets for this study. Detailed acknowledgments are provided in the Supplementary Note.

Author information

Author notes

    • Wen-Hong L Kao
    • , Leena Peltonen
    •  & Steven Wiltshire

    Deceased.

    • Kyle J Gaulton
    • , Teresa Ferreira
    • , Yeji Lee
    • , Anne Raimondo
    • , Reedik Mägi
    •  & Michael E Reschen

    These authors contributed equally to this work.

    • Anna L Gloyn
    • , David Altshuler
    • , Michael Boehnke
    • , Tanya M Teslovich
    • , Mark I McCarthy
    •  & Andrew P Morris

    These authors jointly supervised this work.

Affiliations

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

    • Kyle J Gaulton
    • , Teresa Ferreira
    • , Anubha Mahajan
    • , N William Rayner
    • , Neil Robertson
    • , Nicola L Beer
    • , Martijn van de Bunt
    • , Cecilia M Lindgren
    • , Joseph Trakalo
    • , Steven Wiltshire
    • , Erik Ingelsson
    • , Peter J Donnelly
    • , Anna L Gloyn
    • , Mark I McCarthy
    •  & Andrew P Morris
  2. Department of Genetics, Stanford University, Stanford, California, USA.

    • Kyle J Gaulton
  3. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Yeji Lee
    • , Adam Locke
    • , Laura J Scott
    • , Christian Fuchsberger
    • , Phoenix Kwan
    • , Clement Ma
    • , Hyun Min Kang
    • , Gonçalo R Abecasis
    • , Anne U Jackson
    • , Heather M Stringham
    • , Michael Boehnke
    •  & Tanya M Teslovich
  4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Anne Raimondo
    • , N William Rayner
    • , Neil Robertson
    • , Soren K Thomsen
    • , Jana K Rundle
    • , Nicola L Beer
    • , Martijn van de Bunt
    • , Christopher J Groves
    • , Katharine R Owen
    • , Anna L Gloyn
    •  & Mark I McCarthy
  5. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Reedik Mägi
    • , Tonu Esko
    • , Evelin Mihailov
    • , Andres Metspalu
    •  & Andrew P Morris
  6. Centre for Cellular and Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

    • Michael E Reschen
    • , Anil Chalisey
    •  & Christopher A O'Callaghan
  7. Wellcome Trust Sanger Institute, Hinxton, UK.

    • N William Rayner
    • , Sarah Edkins
    • , Cordelia Langford
    • , Leena Peltonen
    • , Eleftheria Zeggini
    • , Samuli Ripatti
    • , Panagiotis Deloukas
    •  & Inês Barroso
  8. Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.

    • Robert A Scott
    • , Sara M Willems
    • , Nicola D Kerrison
    • , Jian'an Luan
    • , John R B Perry
    • , Ruth J F Loos
    • , Claudia Langenberg
    •  & Nicholas J Wareham
  9. Genomics of Common Disease, Imperial College London, London, UK.

    • Inga Prokopenko
    •  & Philippe Froguel
  10. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Todd Green
    • , Noël P Burtt
    • , Jason Carey
    • , Andrew T Crenshaw
    • , Jason Flannick
    • , Pierre Fontanillas
    • , George B Grant
    • , Cecilia M Lindgren
    • , Leena Peltonen
    • , Sekar Kathiresan
    •  & David Altshuler
  11. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Thomas Sparso
    • , Niels Grarup
    • , Christian T Have
    • , Torben Hansen
    •  & Oluf Pedersen
  12. Lille Institute of Biology, European Genomics Institute of Diabetes, Lille, France.

    • Dorothee Thuillier
    • , Loic Yengo
    • , Stephane Cauchi
    •  & Philippe Froguel
  13. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Harald Grallert
    • , Simone Wahl
    • , Christian Gieger
    • , Norman Klopp
    •  & Thomas Illig
  14. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Harald Grallert
    • , Simone Wahl
    • , Christian Gieger
    • , Barbara Thorand
    •  & Annette Peters
  15. German Center for Diabetes Research, Neuherberg, Germany.

    • Harald Grallert
    • , Simone Wahl
    • , Barbara Thorand
    •  & Annette Peters
  16. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Mattias Frånberg
    • , Rona J Strawbridge
    • , Karl Gertow
    • , Olga McLeod
    • , Bengt Sennblad
    •  & Anders Hamsten
  17. Science for Life Laboratory, Stockholm, Sweden.

    • Mattias Frånberg
    •  & Bengt Sennblad
  18. Department for Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.

    • Mattias Frånberg
  19. Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.

    • Hans Kestler
  20. Medical Systems Biology, Ulm University, Ulm, Germany.

    • Hans Kestler
  21. Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland.

    • Himanshu Chheda
    • , Leena Peltonen
    • , Emmi Tikkanen
    • , Tiinamaija Tuomi
    • , Samuli Ripatti
    •  & Leif C Groop
  22. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.

    • Lewin Eisele
    • , Sonali Pechlivanis
    •  & Susanne Moebus
  23. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Stefan Gustafsson
    •  & Erik Ingelsson
  24. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Valgerdur Steinthorsdottir
    • , Gudmar Thorleifsson
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  25. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Lu Qi
    • , David J Hunter
    • , Peter Kraft
    • , Liming Liang
    •  & Frank B Hu
  26. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Lu Qi
    • , Rob M van Dam
    • , Paul W Franks
    • , David J Hunter
    • , Qi Sun
    •  & Frank B Hu
  27. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Lu Qi
    • , David J Hunter
    • , Qi Sun
    •  & Frank B Hu
  28. Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA.

    • Lu Qi
  29. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Lennart C Karssen
    • , Elisabeth M van Leeuwen
    • , Sara M Willems
    •  & Cornelia van Duijn
  30. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

    • Man Li
    •  & Wen-Hong L Kao
  31. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Han Chen
    • , Ching-Ti Liu
    •  & Josée Dupuis
  32. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Han Chen
    • , Peter Kraft
    •  & Liming Liang
  33. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Michael Linderman
  34. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Yingchang Lu
    •  & Ruth J F Loos
  35. Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  36. Lund University Diabetes Centre, Department of Clinical Science Malmo, Scania University Hospital, Lund University, Malmo, Sweden.

    • Peter Almgren
    • , João Fadista
    • , Paul W Franks
    • , Anna Jonsson
    • , Jasmina Kravic
    • , Eero Lindholm
    • , Valeriya Lyssenko
    • , Nikolay N Oskolkov
    • , Petter Storm
    • , Olle Melander
    • , Peter M Nilsson
    •  & Leif C Groop
  37. Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

    • Damiano Baldassarre
    •  & Elena Tremoli
  38. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.

    • Damiano Baldassarre
    •  & Elena Tremoli
  39. INSERM Centre de Recherche Epidémiologie et Santé des Populations (CESP) U1018, Villejuif, France.

    • Beverley Balkau
  40. University Paris Sud 11, UMRS 1018, Villejuif, France.

    • Beverley Balkau
  41. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Rafn Benediktsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  42. Landspitali University Hospital, Reykjavik, Iceland.

    • Rafn Benediktsson
    • , Astradur B Hreidarsson
    •  & Gunnar Sigurðsson
  43. Integrated Treatment and Research (IFB) Center for Adiposity Diseases, University of Leipzig, Leipzig, Germany.

    • Matthias Blüher
    • , Peter Kovacs
    • , Anke Tonjes
    •  & Michael Stumvoll
  44. Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Matthias Blüher
    • , Peter Kovacs
    • , Anke Tonjes
    •  & Michael Stumvoll
  45. German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.

    • Heiner Boeing
  46. National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Lori L Bonnycastle
    • , Peter S Chines
    •  & Francis S Collins
  47. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Erwin P Bottinger
    • , Omri Gottesman
    •  & Ruth J F Loos
  48. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.

    • Guillaume Charpentier
  49. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Marilyn C Cornelis
  50. Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • David J Couper
  51. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Rob M van Dam
  52. Diabetes Research Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.

    • Alex S F Doney
    •  & Collin N A Palmer
  53. Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.

    • Alex S F Doney
    •  & Collin N A Palmer
  54. Lund University Diabetes Centre, Department of Clinical Science Malmo, Novo Nordisk Scandinavia, Malmo, Sweden.

    • Mozhgan Dorkhan
  55. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Johan G Eriksson
    • , Leena Kinnunen
    • , Satu Männistö
    • , Leena Peltonen
    • , Veikko Salomaa
    • , Heikki Koistinen
    •  & Jaakko Tuomilehto
  56. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson
  57. Unit of General Practice, Helsinki University General Hospital, Helsinki, Finland.

    • Johan G Eriksson
  58. Folkhalsan Research Center, Helsinki, Finland.

    • Johan G Eriksson
    •  & Tiinamaija Tuomi
  59. Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA.

    • Tonu Esko
  60. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Tonu Esko
    •  & Jose C Florez
  61. CNRS UMR 8199, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.

    • Elodie Eury
    • , Stéphane Lobbens
    •  & Philippe Froguel
  62. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Caroline Fox
    •  & Josée Dupuis
  63. Division of Endocrinology and Metabolism, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline Fox
  64. Department of Clinical Sciences, Lund University, Malmo, Sweden.

    • Paul W Franks
  65. Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden.

    • Paul W Franks
  66. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Bruna Gigante
    • , Karin Leander
    •  & Ulf de Faire
  67. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

    • Maija Hassinen
    • , Timo A Lakka
    •  & Rainer Rauramaa
  68. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany.

    • Christian Herder
    •  & Michael Roden
  69. German Center for Diabetes Research, partner site Dusseldorf, Dusseldorf, Germany.

    • Christian Herder
    •  & Michael Roden
  70. Nord-Trøndelag Health Study (HUNT) Research Center, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.

    • Oddgeir L Holmen
    • , Carl G P Platou
    •  & Kristian Hveem
  71. Cardiovascular Genetics, British Heart Foundation (BHF) Laboratories, Institute of Cardiovascular Sciences, University College London, London, UK.

    • Steve E Humphries
  72. Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • David J Hunter
    •  & Peter Kraft
  73. Steno Diabetes Center, Gentofte, Denmark.

    • Marit E Jørgensen
    •  & Valeriya Lyssenko
  74. Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.

    • Torben Jørgensen
    •  & Allan Linneberg
  75. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Torben Jørgensen
  76. Faculty of Medicine, University of Aalborg, Aalborg, Denmark.

    • Torben Jørgensen
  77. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.

    • Norman Klopp
    •  & Thomas Illig
  78. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Peter Lichtner
  79. Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

    • Allan Linneberg
  80. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Allan Linneberg
  81. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Julia Meyer
    • , Martina Müller-Nurasyid
    •  & Konstantin Strauch
  82. Biomedical Research Centre Genomics Core Facility, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, Guy's & St Thomas' Hospital, London, UK.

    • Ghazala Mirza
  83. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Thomas W Mühleisen
    •  & Markus M Nöthen
  84. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Thomas W Mühleisen
    •  & Markus M Nöthen
  85. Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.

    • Thomas W Mühleisen
  86. Department of Medicine I, University Hospital Grosshadern, Ludwig Maximilians Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  87. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Neuherberg, Germany.

    • Martina Müller-Nurasyid
    •  & Konstantin Strauch
  88. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

    • Martina Müller-Nurasyid
    •  & Annette Peters
  89. Department of Epidemiology, Murcia Regional Health Council, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.

    • Carmen Navarro
  90. Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

    • Carmen Navarro
  91. Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.

    • Carmen Navarro
  92. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Katharine R Owen
    • , Anna L Gloyn
    •  & Mark I McCarthy
  93. Cancer Research and Prevention Institute (ISPO), Florence, Italy.

    • Domenico Palli
  94. Department of Internal Medicine, Levanger Hospital, Nord-Trondelag Health Trust, Levanger, Norway.

    • Carl G P Platou
  95. Department of Endocrinology and Diabetology, University Hospital Dusseldorf, Dusseldorf, Germany.

    • Michael Roden
  96. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Douglas Ruderfer
  97. Boston University Data Coordinating Center, Boston, Massachusetts, USA.

    • Denis Rybin
  98. University Medical Center Utrecht, Utrecht, the Netherlands.

    • Yvonne T van der Schouw
  99. Icelandic Heart Association, Kopavogur, Iceland.

    • Gunnar Sigurðsson
  100. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Alena Stančáková
    • , Johanna Kuusisto
    •  & Markku Laakso
  101. Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany.

    • Gerald Steinbach
  102. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.

    • Emmi Tikkanen
    •  & Samuli Ripatti
  103. Department of Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.

    • Tiinamaija Tuomi
  104. Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

    • Tiinamaija Tuomi
  105. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Roman Wennauer
    •  & Eric Sijbrands
  106. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

    • Andrew R Wood
    •  & Timothy M Frayling
  107. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.

    • Ian Dunham
    •  & Ewan Birney
  108. Division of Endocrinology, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain.

    • Lorenzo Pasquali
  109. Josep Carreras Leukaemia Research Institute, Badalona, Spain.

    • Lorenzo Pasquali
  110. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.

    • Lorenzo Pasquali
  111. Department of Medicine, Imperial College London, London, UK.

    • Jorge Ferrer
  112. Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centre Esther Koplowitz, Barcelona, Spain.

    • Jorge Ferrer
  113. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  114. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jose C Florez
    • , James B Meigs
    •  & David Altshuler
  115. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jose C Florez
    • , Sekar Kathiresan
    •  & David Altshuler
  116. Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jose C Florez
    •  & David Altshuler
  117. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  118. Human Genome Sequencing Center at Baylor College of Medicine, Houston, Texas, USA.

    • Eric Boerwinkle
  119. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • James S Pankow
  120. Netherlands Genomics Initiative, Netherlands Consortium for Healthy Ageing and Center for Medical Systems Biology, Rotterdam, the Netherlands.

    • Cornelia van Duijn
  121. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • James B Meigs
  122. Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Finland.

    • Timo A Lakka
    •  & Karl-Heinz Jöcke
  123. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.

    • Timo A Lakka
    •  & Rainer Rauramaa
  124. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Nancy L Pedersen
  125. Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.

    • Lars Lind
  126. Faculty of Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Sirkka M Keinanen-Kiukaanniemi
  127. Unit of General Practice, Oulu University Hospital, Oulu, Finland.

    • Sirkka M Keinanen-Kiukaanniemi
  128. South Ostrobothnia Central Hospital, Seinajoki, Finland.

    • Eeva Korpi-Hyövälti
  129. Finnish Diabetes Association, Tampere, Finland.

    • Timo E Saaristo
  130. Pirkanmaa District Hospital, Tampere, Finland.

    • Timo E Saaristo
  131. Department of Medicine, Central Finland Central Hospital, Jyvasklya, Finland.

    • Juha Saltevo
  132. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Andres Metspalu
  133. Clinic of Cardiology, West German Heart Centre, University Hospital of Essen, University Duisdurg-Essen, Essen, Germany.

    • Raimund Erbel
  134. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Samuli Ripatti
  135. Division of Endocrinology and Diabetes, Department of Internal Medicine, University Medical Centre Ulm, Ulm, Germany.

    • Bernhard O Boehm
  136. Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore.

    • Bernhard O Boehm
  137. Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Richard N Bergman
  138. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke
  139. Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.

    • Heikki Koistinen
  140. Minerva Foundation Institute for Medical Research, Helsinki, Finland.

    • Heikki Koistinen
  141. Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.

    • Jaakko Tuomilehto
  142. Centre for Vascular Prevention, Danube University Krems, Krems, Austria.

    • Jaakko Tuomilehto
  143. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Jaakko Tuomilehto
  144. Department of Community Medicine, Faculty of Health Sciences, University of Tromso, Tromso, Norway.

    • Inger Njølstad
  145. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Panagiotis Deloukas
  146. Department of Statistics, University of Oxford, Oxford, UK.

    • Peter J Donnelly
  147. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

    • Andrew T Hattersley
  148. Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.

    • Rob Sladek
  149. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.

    • Rob Sladek
  150. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

    • Torben Hansen
  151. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • Andrew D Morris
  152. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  153. University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, UK.

    • Inês Barroso
  154. National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.

    • Inês Barroso
  155. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  156. Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  157. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  158. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

    • Andrew P Morris

Consortia

  1. the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

    A list of members and affiliations appears in the Supplementary Note.

Authors

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Contributions

Writing group. K.J.G., T.F., Y. Lee, A.R., R.M., M.E.R., A.L.G., D.A., M. Boehnke, T.M.T., M.I.M., A.P.M. Central meta-analysis group. K.J.G., T.F., Y. Lee, R.M., A. Mahajan, A. Locke, N.W.R., N.R., T.M.T., M.I.M., A.P.M. Annotation and functional analysis group. K.J.G., A.R., M.E.R., S.K.T., J.K.R., N.L.B., M.v.d.B., A.C., I.D., E. Birney, L. Pasquali, J. Ferrer, C.A.O'C., A.L.G., M.I.M. Validation meta-analysis group. R.M., R.A.S., I.P., L.J.S., A.P.M. Metabochip cohort-level primary analysis. Y. Lee, T.G., T.S., D.T., L.Y., H.G., S. Wahl, M.F., R.J.S., H. Kestler, H. Chheda, L.E., S.G., T.M.T., A.P.M. Validation cohort-level primary analysis. V. Steinthorsdottir, G.T., L.Q., L.C.K., E.M.v.L., S.M.W., M. Li, H. Chen, C. Fuchsberger, P. Kwan, C.M., M. Linderman, Y. Lu. Metabochip design. H.M.K., B.F.V. Cohort sample collection, genotyping, phenotyping or additional analysis. B.F.V., G.R.A., P.A., D.B., B.B., R.B., M. Blüher, H.B., L.L.B., E.P.B., N.P.B., J.C., G.C., P.S.C., M.C.C., D.J.C., A.T.C., R.M.v.D., A.S.F.D., M.D., S.E., J.G.E., T.E., E.E., J. Fadista, J. Flannick, P. Fontanillas, C. Fox, P.W.F., K.G., C.G., B.G., O.G., G.B.G., N.G., C.J.G., M.H., C.T.H., C.H., O.L.H., A.B.H., S.E.H., D.J.H., A.U.J., A.J., M.E.J., T.J., W.-H.L.K., N.D.K., L.K., N.K., A.K., P. Kovacs, P. Kraft, J. Kravic, C. Langford, K.L., L. Liang, P.L., C.M.L., E.L., A. Linneberg, C.-T.L., S.L., J.L., V.L., S. Männistö, O. McLeod, J.M., E.M., G.M., T.W.M., M.M.-N., C.N., M.M.N., N.N.O., K.R.O., D.P., S.P., L. Peltonen, J.R.B.P., C.G.P.P., M.R., D. Ruderfer, D. Rybin, Y.T.v.d.S., B.S., G. Sigur∂sson, A.S., G. Steinbach, P.S., K. Strauch, H.M.S., Q.S., B.T., E. Tikkanen, A.T., J. Trakalo, E. Tremoli, T.T., R.W., S. Wiltshire, A.R.W., E.Z. Validation cohort principal investigators. R.J.F.L., J.D., J.C.F., E. Boerwinkle, J.S.P., C.v.D., E.S., J.B.M., F.B.H., U.T., K. Stefansson, P.D., P.J.D., T.M.F., A.T.H., I.B., C. Langenberg, N.J.W., M. Boehnke, M.I.M. Metabochip cohort principal investigators. T.A.L., R.R., M.S., N.L.P., L. Lind, S.M.K.-K., E.K.-H., T.E.S., J.S., J. Kuusisto, M. Laakso, A. Metspalu, R.E., K.-H.J., S. Moebus, S.R., V. Salomaa, E.I., B.O.B., R.N.B., F.S.C., K.L.M., H. Koistinen, J. Tuomilehto, K.H., I.N., P.D., P.J.D., T.M.F., A.T.H., U.d.F., A.H., T.I., A.P., S.C., R.S., P. Froguel, O.P., T.H., A.D.M., C.N.A.P., S.K., O. Melander, P.M.N., L.C.G., I.B., C. Langenberg, N.J.W., D.A., M. Boehnke, M.I.M. Project management. K.J.G., A.L.G., D.A., M. Boehnke, T.M.T., M.I.M., A.P.M. DIAGRAM Consortium management. D.A., M. Boehnke, M.I.M.

Competing interests

V. Steinthorsdottir, G.T., A.K., U.T. and K. Stefansson are employed by deCODE Genetics/Amgen, Inc. I.B. and spouse own stock in GlaxoSmithKline and Incyte.

Corresponding authors

Correspondence to Kyle J Gaulton or Mark I McCarthy or Andrew P Morris.

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https://doi.org/10.1038/ng.3437

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