Letter | Published:

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Nature Genetics volume 43, pages 11311138 (2011) | Download Citation

Abstract

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

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Acknowledgements

We thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of data. We also thank the research participants who took part in these studies. Major support for the work came from European Commission (FP5, FP6 and FP7); European Science Foundation; European Science Council; US NIH; US National Institute of Mental Health; US NIDDK; Genetic Association Information Network; US National Institute on Aging; US National Human Genome Research Institute; US NHLBI; UK NIHR; NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; NIHR Comprehensive Biomedical Research Centre Guy's and St. Thomas' NHS Trust; UK Biotechnology and Biological Sciences Research Council; UK MRC; British Heart Foundation; Wellcome Trust; Swiss National Science Foundation; Academy of Finland; Finnish Cardiovascular Research Foundation; Swedish Research Council; Swedish Heart-Lung Foundation; Helmholtz Zentrum München; German Research Center for Environmental Health; German Federal Ministry of Education and Research; German National Genome Research Network; Netherlands Organization for Scientific Research; Dutch Ministries of Economic Affairs, of Education, Culture and Science, for Health, Welfare and Sports; Netherlands Organization for Health Research and Development; Economic Structure Enhancing Fund of the Dutch government; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Dutch Brain Foundation; Dutch Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Canadian Institutes for Health Research; Ontario Research Fund; The Barts and the London Charity; University Medical Center Groningen; University of Groningen; University of Oulu, Biocenter Oulu; University Hospital Oulu; Biocentrum Helsinki; Erasmus Medical Center and Erasmus University, Rotterdam; Karolinska Institutet; Stockholm County Council; Municipality of Rotterdam; Federal State of Mecklenburg-West Pomerania; AstraZeneca; GlaxoSmithKline; Siemens Healthcare; Novo Nordisk Foundation; Yrjö Jahnsson Foundation; Biomedicum Helsinki Foundation; Gyllenberg Foundation; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Söderberg Foundation; Robert Dawson Evans Endowment, Boston University School of Medicine; Instrumentarium Science Foundation; Jenny and Antti Wihuri Foundation and the Canadian Primary Biliary Cirrhosis Society. A full list of acknowledgments is provided in the Supplementary Note.

Author information

Author notes

    • John C Chambers
    • , Weihua Zhang
    • , Joban Sehmi
    • , Xinzhong Li
    • , Mark N Wass
    • , Pim Van der Harst
    • , Hilma Holm
    • , Serena Sanna
    • , Maryam Kavousi
    • , Mika Ala-Korpela
    • , Kari Stefansson
    • , Peter Vollenweider
    • , Henry Völzke
    • , Eric E Schadt
    • , James Scott
    • , Marjo-Riitta Järvelin
    • , Paul Elliott
    •  & Jaspal S Kooner

    These authors contributed equally to this work.

Affiliations

  1. Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK.

    • John C Chambers
    • , Weihua Zhang
    • , Lachlan J Coin
    • , Paul F O'Reilly
    • , Pimphen Charoen
    • , Srijita Sen-Chowdhry
    • , Taru Tukiainen
    • , Peter Würtz
    • , Marjo-Riitta Järvelin
    •  & Paul Elliott
  2. Imperial College Healthcare National Health Service (NHS) Trust, London, UK.

    • John C Chambers
    • , Howard C Thomas
    •  & Jaspal S Kooner
  3. Ealing Hospital NHS Trust, Middlesex, UK.

    • John C Chambers
    • , Weihua Zhang
    • , Joban Sehmi
    • , Debashish Das
    •  & Jaspal S Kooner
  4. National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

    • Joban Sehmi
    • , James Scott
    •  & Jaspal S Kooner
  5. Institute of Clinical Science, Imperial College London, Royal Brompton Hospital, London, UK.

    • Xinzhong Li
  6. Structural Bioinformatics Group, Division of Molecular Biosciences, Imperial College London, South Kensington, London, UK.

    • Mark N Wass
    •  & Michael J E Sternberg
  7. Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands.

    • Pim Van der Harst
    •  & Irene Mateo Leach
  8. deCODE genetics, Reykjavik, Iceland.

    • Hilma Holm
    • , Gudmar Thorleifsson
    • , Daniel F Gudbjartsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  9. Istituto di Ricerca Genetica e Biomedica del Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.

    • Serena Sanna
    • , Francesco Cucca
    • , Sandra Lai
    •  & Manuela Uda
  10. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Maryam Kavousi
    • , Albert Hofman
    • , Harry L A Janssen
    • , Andre G Uitterlinden
    • , Cornelia M van Duijn
    •  & Jacqueline C M Witteman
  11. Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Health Aging, Rotterdam, The Netherlands.

    • Maryam Kavousi
    • , Albert Hofman
    • , Andre G Uitterlinden
    • , Cornelia M van Duijn
    •  & Jacqueline C M Witteman
  12. Institute for Community Medicine, University of Greifswald, Germany.

    • Sebastian E Baumeister
    •  & Henry Völzke
  13. Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.

    • Guohong Deng
    •  & Wenting Tan
  14. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
    •  & Brigitte Kühnel
  15. Department of Neurology, Boston University School of Medicine, Boston Massachusetts, USA.

    • Nancy L Heard-Costa
  16. Department of Biological Psychology, VU University Amsterdam (VUA), Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga
    • , Eco J C de Geus
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  17. Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

    • Vinod Kumar
    • , Yusuke Nakamura
    •  & Koichi Matsuda
  18. Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Vasiliki Lagou
    • , Behrooz Z Alizadeh
    • , Bram P Prins
    •  & Harold Snieder
  19. Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.

    • Vasiliki Lagou
    • , Nilufer Rahmioglu
    • , Inga Prokopenko
    •  & Mark I McCarthy
  20. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Vasiliki Lagou
    • , Inga Prokopenko
    •  & Mark I McCarthy
  21. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Liming Liang
  22. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Liming Liang
  23. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke′s Hospital, Cambridge UK.

    • Jian'an Luan
    • , Nita G Forouhi
    • , Ruth J F Loos
    •  & Nicholas J Wareham
  24. Institute of Social and Preventive Medicine (IUMSP), University Hospital and University of Lausanne, Lausanne, Switzerland.

    • Pedro Marques Vidal
  25. Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • John F Peden
    • , Martin Farrall
    •  & Hugh Watkins
  26. Computational Medicine Research Group, Institute of Clinical Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.

    • Pasi Soininen
    • , Antti J Kangas
    • , Markku J Savolainen
    • , Taru Tukiainen
    • , Peter Würtz
    •  & Mika Ala-Korpela
  27. Nuclear Magnetic Resonance (NMR) Metabonomics Laboratory, Department of Biosciences, University of Eastern Finland, Kuopio, Finland.

    • Pasi Soininen
    •  & Mika Ala-Korpela
  28. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.

    • Elizabeth K Speliotes
  29. Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

    • Elizabeth K Speliotes
  30. Genetics, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Xin Yuan
    • , Vincent Mooser
    •  & Dawn M Waterworth
  31. Boston University School of Medicine, Boston, Massachusetts, USA.

    • Larry D Atwood
    •  & Kiran Musunuru
  32. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri, USA.

    • Ingrid B Borecki
  33. The Diabetes Inflammation Laboratory, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK.

    • Morris J Brown
    •  & Chris Wallace
  34. Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

    • Pimphen Charoen
  35. Neuroscience Campus Amsterdam, VUA and VUA Medical Center, Amsterdam, The Netherlands.

    • Eco J C de Geus
  36. National Heart and Lung Institute, Imperial College London, London, UK.

    • Anna L Dixon
    • , Miriam F Moffatt
    •  & William O Cookson
  37. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Angela Döring
    •  & H-Erich Wichmann
  38. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Georg Ehret
  39. IUMSP, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.

    • Georg Ehret
  40. Cardiology, Department of Medicine, Geneva University Hospital, Geneva, Switzerland.

    • Georg Ehret
  41. The Laboratory in Mjodd, Reykjavik, Iceland.

    • Gudmundur I Eyjolfsson
  42. Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • Martin Farrall
    •  & Hugh Watkins
  43. Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Germany.

    • Nele Friedrich
    •  & Henri Wallaschofski
  44. Genetics and Gastroenterology Divisions, Brigham and Women′s Hospital, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Wolfram Goessling
  45. Harvard Medical School, Boston, Massachusetts, USA.

    • Wolfram Goessling
  46. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.

    • Wolfram Goessling
  47. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, US National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Tamara B Harris
  48. Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Anneli Pouta
  49. CEA-IG Centre National de Genotypage, Evry Cedex, France.

    • Simon Heath
    •  & Mark Lathrop
  50. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Gideon M Hirschfield
    •  & Katherine A Siminovitch
  51. Liver Center, Toronto Western Hospital, Toronto, Ontario, Canada.

    • Gideon M Hirschfield
  52. Centre for Liver Research, University of Birmingham, Birmingham, UK.

    • Gideon M Hirschfield
  53. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.

    • Georg Homuth
  54. Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London, UK.

    • Elina Hyppönen
  55. Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Harry L A Janssen
    •  & Jeoffrey N L Schouten
  56. Clinical Pharmacology and The Genome Center, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Toby Johnson
    • , Patricia B Munroe
    •  & Mark Caulfield
  57. Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Ido P Kema
  58. Institute of Diagnostic Radiology and Neuroradiology, University of Greifswald, Greifswald, Germany.

    • Jens P Kühn
    •  & Ralf Puls
  59. Fondation Jean Dausset Ceph, Paris, France.

    • Mark Lathrop
  60. Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

    • Markus M Lerch
  61. Department of Genetics, Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Yun Li
  62. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.

    • T Jake Liang
  63. Office of Biostatistics Research, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA.

    • Jing-Ping Lin
  64. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Nicholas G Martin
    • , Grant W Montgomery
    •  & John B Whitfield
  65. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Kiran Musunuru
  66. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Kiran Musunuru
  67. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Kiran Musunuru
  68. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kiran Musunuru
  69. NHLBI Framingham Heart Study, Framingham, Massachusetts, USA.

    • Christopher J O'Donnell
    •  & Caroline S Fox
  70. Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland.

    • Isleifur Olafsson
  71. Department of Psychiatry and EMGO Institute for Health and Care Research, VUA Medical Centre, Amsterdam, The Netherlands.

    • Brenda W Penninx
    •  & Johannes H Smit
  72. Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.

    • Brenda W Penninx
  73. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Brenda W Penninx
  74. Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland.

    • Anneli Pouta
    •  & Marjo-Riitta Järvelin
  75. Institute of Diagnostics, Clinical Chemistry, University of Oulu, Oulu, Finland.

    • Aimo Ruokonen
  76. Department of Internal Medicine and Biocenter Oulu, Clinical Research Center, University of Oulu, Oulu, Finland.

    • Markku J Savolainen
    •  & Mika Ala-Korpela
  77. Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.

    • David Schlessinger
  78. Gesellschaft für Arterioskleroseforschung, Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany.

    • Udo Seedorf
  79. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

    • Katherine A Siminovitch
  80. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Katherine A Siminovitch
  81. Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.

    • Katherine A Siminovitch
  82. Toronto General Research Institute, Toronto, Ontario, Canada.

    • Katherine A Siminovitch
  83. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Timothy D Spector
    •  & Kourosh R Ahmadi
  84. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Tanya M Teslovich
    •  & Goncalo R Abecasis
  85. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Andre G Uitterlinden
  86. Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Melanie M Van der Klauw
    •  & Bruce H R Wolffenbuttel
  87. LifeLines Cohort Study and Biobank, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Melanie M Van der Klauw
    • , Michael J E Sternberg
    •  & Bruce H R Wolffenbuttel
  88. Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  89. Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  90. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H-Erich Wichmann
  91. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  92. EMGO+ Institute, VUA Medical Center, Amsterdam, The Netherlands.

    • Gonneke Willemsen
    •  & Dorret I Boomsma
  93. Samuel Lunenfeld and Toronto General Research Institutes, Toronto, Ontario, Canada.

    • Chun Xu
  94. Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Laura M Yerges-Armstrong
  95. Center for Medical Systems Biology, Rotterdam, The Netherlands.

    • Cornelia M van Duijn
  96. Genomics of Common Diseases, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

    • Philippe Froguel
  97. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  98. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Christa Meisinger
  99. Obesity Research Unit, Department of Medicine, Division of Internal Medicine, Helsinki University Hospital, Helsinki, Finland.

    • Kirsi H Pietiläinen
  100. The Institute for Molecular Medicine FIMM, Helsinki, Finland.

    • Kirsi H Pietiläinen
  101. Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Kirsi H Pietiläinen
  102. MRC-Social Genetic Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, King's College, London, UK.

    • Gunter Schumann
  103. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Ronald P Stolk
  104. Faculty of Medicine, Imperial College London, London, UK.

    • Howard C Thomas
  105. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  106. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Gérard Waeber
    •  & Peter Vollenweider
  107. Division of Endocrinology, Hypertension, and Metabolism, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Caroline S Fox
  108. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Eric E Schadt
  109. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  110. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  111. MRC–Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Marjo-Riitta Järvelin
    •  & Paul Elliott

Consortia

  1. Alcohol Genome-wide Association (AlcGen) Consortium

    A full list of members is given in Supplementary Note.

  2. Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study

    A full list of members is given in Supplementary Note.

  3. Genetic Investigation of Anthropometric Traits (GIANT) Consortium

    A full list of members is given in Supplementary Note.

  4. Global Lipids Genetics Consortium

    A full list of members is given in Supplementary Note.

  5. Genetics of Liver Disease (GOLD) Consortium

    A full list of members is given in Supplementary Note.

  6. International Consortium for Blood Pressure (ICBP-GWAS)

    A full list of members is given in Supplementary Note.

  7. Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC)

    A full list of members is given in Supplementary Note.

Authors

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Contributions

Study organization and manuscript preparation was done by J.C.C., W.Z., J. Sehmi, X.L., M.N.W., P.V.d.H., H.H., S.S., M.K., M.A.-K., K.S., P.V., H.V., E.E.S., J. Scott, M.-R.J., P.E. and J.S.K. All authors reviewed and had the opportunity to comment on the manuscript. Data collection and analysis in the participating GWASs were done by G.W.M., J.B.W. and N.G.M. (Australian Twin Cohort); C.W., M.C., M.J.B. and P.B.M. (BRIGHT); D.M.W., G. Waeber, P.M.V., P.V., V.M. and X.Y. (CoLaus); D.F.G., G.I.E., G.T., H.H., I.O., K.S. and U.T. (deCODE); J.L., N.G.F., N.J.W. and R.J.F.L. (Fenland); K.H.P. (Finnish Twin Cohort); C.J.O., C.S.F., J.P.L., L.D.A., N.L.H.-C., R.S.V., T.J.L. and W.G. (Framingham Heart Study); A.D., B.K., C.G., C.M. and H.-E.W. (KORA); B.H.R.W., I.M.L., I.P.K., M.M.V.d.K., P.V.d.H. and R.P.S. (LIFELINES); D.D., G.D., H.C.T., I.P., J.C.C., J. Scott, J. Sehmi, J.S.K., M.I.M., P.E., P.F., S.S.-C., W.Z., X.L. and Y.L. (LOLIPOP); B.P.P., B.W.P., B.Z.A., H.S., J.H.S. and V.L. (NESDA); D.I.B., E.J.C.d.G., G. Willemsen, J.-J.H. (Netherlands Twins Register); A.-L.H., A.P., A.R., E.H., M.-R.J. and P.F.O. (Northern Finland Birth Cohort 1966); H. Watkins, J.F.P., M.F. and U.S. (PROCARDIS); A.G.U., A.H., C.M.v.D., H.L.A.J., J.C.M.W., J.N.L.S. and M.K. (Rotterdam Study 1); D.S., F.C., G.R.A., M.U., S.L. and S.S. (SardiNIA); G.H., H.V., H. Wallaschofski, J.P.K., M.M.L., N.F., R.P. and S.E.B. (SHIP); K.R.A., N.R. and T.D.S. (TwinsUK). Biologic associations of loci and bioinformatics were carried out by G.D., W.T., K. Matsuda, V.K., Y.N. and by G.S., L.J.C., P.C. (AlcGen Consortium), C.X., G.M.H., K.A.S. (Canadian Primary Biliary Cirrhosis Consortium), K. Musunuru, T.M.T. (Global Lipids Consortium), E.K.S., I.B.B., L.M.Y.A., T.B.H. (GOLD consortium) and G.E. and T.J. (ICBP-GWAS). Gene expression analyses were done by E.E.S., A.L.D., H.H., G.T., L.L., M.F.M., M.L., S.H. and W.O.C. Metabonomic analyses were done by A.J.K., M.A.-K., M.J.S., P.S., P.W. and T.T. Structural biology was done by M.J.E.S. and M.N.W.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to John C Chambers or Paul Elliott or Jaspal S Kooner.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–20 and Supplementary Figures 1–6 and Supplementary Note.

About this article

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DOI

https://doi.org/10.1038/ng.970

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