Biological, clinical and population relevance of 95 loci for blood lipids

Journal name:
Nature
Volume:
466,
Pages:
707–713
Date published:
DOI:
doi:10.1038/nature09270
Received
Accepted

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5×10−8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

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Author information

  1. These authors contributed equally to this work.

    • Tanya M. Teslovich,
    • Kiran Musunuru,
    • L. Adrienne Cupples,
    • Manjinder S. Sandhu,
    • Paul M Ridker,
    • Daniel J. Rader,
    • Cornelia M. van Duijn,
    • Gonçalo R. Abecasis,
    • Michael Boehnke &
    • Sekar Kathiresan

Affiliations

  1. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Tanya M. Teslovich,
    • Cristen J. Willer,
    • Heather M. Stringham,
    • Gonçalo R. Abecasis &
    • Michael Boehnke
  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Kiran Musunuru,
    • James P. Pirruccello,
    • Benjamin F. Voight,
    • David Altshuler &
    • Sekar Kathiresan
  3. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Kiran Musunuru &
    • Sekar Kathiresan
  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Kiran Musunuru,
    • Daniel I. Chasman,
    • Robert Y. L. Zee,
    • Christopher J. O’Donnell,
    • David Altshuler,
    • Paul M Ridker &
    • Sekar Kathiresan
  5. Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Kiran Musunuru,
    • James P. Pirruccello,
    • Benjamin F. Voight,
    • Candace Guiducci,
    • Elena Gonzalez,
    • Kenechi G. Ejebe,
    • Gabriel Crawford,
    • Noel P. Burtt,
    • David Altshuler,
    • Stacey B. Gabriel &
    • Sekar Kathiresan
  6. Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

    • Kiran Musunuru &
    • James P. Pirruccello
  7. Icelandic Heart Association, Heart Preventive Clinic and Research Institute, 201 Kopavogur, Iceland.

    • Albert V. Smith &
    • Vilmundur Gudnason
  8. University of Iceland, 101 Reykjavik, Iceland.

    • Albert V. Smith,
    • Unnur Thorsteinsdottir,
    • Vilmundur Gudnason &
    • Kari Stefansson
  9. Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Andrew C. Edmondson,
    • Mingyao Li,
    • Muredach P. Reilly &
    • Daniel J. Rader
  10. Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Andrew C. Edmondson,
    • Ioannis M. Stylianou,
    • Mingyao Li,
    • Muredach P. Reilly &
    • Daniel J. Rader
  11. Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.

    • Masahiro Koseki,
    • David Masson &
    • Alan R. Tall
  12. Institute for Molecular Medicine Finland FIMM, University of Helsinki, FI-00014 Helsinki, Finland.

    • Samuli Ripatti,
    • Ida Surakka,
    • Kaisa Silander,
    • Juha Saharinen,
    • Markus Perola &
    • Jaakko Kaprio
  13. National Institute for Health and Welfare, P.O. Box 104, FI-00251 Helsinki, Finland.

    • Samuli Ripatti,
    • Ida Surakka,
    • Kaisa Silander,
    • Markus Perola &
    • Jaakko Kaprio
  14. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston Massachusetts 02215, USA.

    • Daniel I. Chasman,
    • Robert Y. L. Zee,
    • Lynda M. Rose &
    • Paul M Ridker
  15. Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.

    • Christopher T. Johansen &
    • Robert A. Hegele
  16. Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

    • Sigrid W. Fouchier,
    • G. Kees Hovingh &
    • John J.P. Kastelein
  17. Department of Epidemiology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

    • Aaron Isaacs,
    • Yurii S. Aulchenko,
    • Jacqueline C. M. Witteman,
    • Andre G. Uitterlinden,
    • Eric J. G. Sijbrands,
    • A. Cecile J. W. Janssens,
    • Albert Hofman &
    • Cornelia M. van Duijn
  18. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.

    • Gina M. Peloso,
    • Serkalem Demissie &
    • L. Adrienne Cupples
  19. National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts 01702, USA.

    • Gina M. Peloso,
    • Christopher J. O’Donnell,
    • Serkalem Demissie &
    • L. Adrienne Cupples
  20. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

    • Maja Barbalic &
    • Eric Boerwinkle
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    • Robert Luben,
    • Kay-Tee Khaw &
    • Manjinder S. Sandhu
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    • Joshua C. Bis
  23. deCODE Genetics, 101 Reykjavik, Iceland.

    • Gudmar Thorleifsson,
    • Hilma Holm,
    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  24. Division of Statistical Genomics in the Center for Genome Sciences, Washington University School of Medicine, St Louis, Missouri 63108, USA.

    • Mary F. Feitosa &
    • Ingrid B. Borecki
  25. Department of Epidemiology and Public Health, Imperial College London, London W2 1PG, UK.

    • John Chambers &
    • Weihua Zhang
  26. Department of Clinical Sciences, Lund University, SE-20502, Malmö, Sweden.

    • Marju Orho-Melander,
    • Olle Melander &
    • Leif C. Groop
  27. Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.

    • Toby Johnson &
    • Mark J. Caulfield
  28. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

    • Xiaohui Li,
    • Xiuqing Guo,
    • Talin Haritunians,
    • Yii-der I. Chen &
    • Jerome I. Rotter
  29. Center for Genome Science, National Institute of Health, Seoul 122-701, Republic of Korea.

    • Yoon Shin Cho,
    • Min Jin Go,
    • Young Jin Kim &
    • Jong-Young Lee
  30. Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.

    • Taesung Park
  31. Department of Statistics, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.

    • Taesung Park
  32. Department of Statistics, Sookmyung Women’s University, Seoul 140-742, Republic of Korea.

    • Kyunga Kim
  33. Centre for Molecular Epidemiology, National University of Singapore, Singapore 117597, Republic of Singapore.

    • Xueling Sim
  34. Genome Institute of Singapore, Singapore 138672, Republic of Singapore.

    • Rick Twee-Hee Ong &
    • Mark Seielstad
  35. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Damien C. Croteau-Chonka,
    • Leslie A. Lange &
    • Karen L. Mohlke
  36. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

    • Joshua D. Smith,
    • Mark Rieder &
    • Deborah A. Nickerson
  37. Genetics Division, GlaxoSmithKline R&D, King of Prussia, Pennsylvania 19406, USA.

    • Kijoung Song,
    • Xin Yuan,
    • Dawn M. Waterworth &
    • Vincent Mooser
  38. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.

    • Jing Hua Zhao,
    • Jian’an Luan,
    • Nicholas J. Wareham,
    • Ruth J. F. Loos,
    • Claudia Langenberg &
    • Manjinder S. Sandhu
  39. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria.

    • Claudia Lamina &
    • Florian Kronenberg
  40. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, 23562 Lübeck, Germany.

    • Andreas Ziegler &
    • Inke R. König
  41. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.

    • Alan F. Wright,
    • Veronique Vitart,
    • Caroline Hayward &
    • Nicholas D. Hastie
  42. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA) and Center of Medical Systems Biology (CMSB), 2300 RC Leiden, The Netherlands.

    • Jacqueline C. M. Witteman,
    • Andre G. Uitterlinden,
    • Albert Hofman &
    • Cornelia M. van Duijn
  43. Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.

    • James F. Wilson,
    • Igor Rudan &
    • Harry Campbell
  44. Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands.

    • Gonneke Willemsen,
    • Jouke-Jan Hottenga,
    • Eco J. C. de Geus &
    • Dorret I. Boomsma
  45. Institute of Epidemiology, Helmholtz Zentrum Munchen – German Research Center for Environmental Health, 85764 Neuherberg, Germany.

    • H.-Erich Wichmann,
    • Iris M. Heid,
    • Christian Gieger &
    • Angela Döring
  46. Genetic Epidemiology Unit, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland 4029, Australia.

    • John B. Whitfield,
    • Grant W. Montgomery &
    • Nicholas G. Martin
  47. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.

    • Gérard Waeber &
    • Peter Vollenweider
  48. Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

    • Andre G. Uitterlinden &
    • Eric J. G. Sijbrands
  49. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.

    • Manuela Uda &
    • Serena Sanna
  50. Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.

    • Jaakko Tuomilehto,
    • Veikko Salomaa &
    • Aki S. Havulinna
  51. Department of Health Sciences, University of Leicester, Leicester LE1 6TP, UK.

    • John R. Thompson
  52. Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.

    • Toshiko Tanaka
  53. Medstar Research Institute, Baltimore, Maryland 21218, USA.

    • Toshiko Tanaka
  54. Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK.

    • Tim D. Spector,
    • Nicole Soranzo &
    • Massimo Mangino
  55. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Nicole Soranzo,
    • Panagiotis Deloukas,
    • Inês Barroso &
    • Manjinder S. Sandhu
  56. Department of Psychiatry, EMGO Institute, Neuroscience Campus Amsterdam, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.

    • Johannes H. Smit &
    • Brenda W. J. H. Penninx
  57. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), FI-00029 Helsinki, Finland.

    • Juha Sinisalo &
    • Markku S. Nieminen
  58. Unita Operativa Geriatria, Istituto Nazionale Ricovero e Cura Anziani (INRCA), Istituto Ricovero e Cura a Carattere Scientifico (IRCCS), Via Cassia 1167, 00189 Rome, Italy.

    • Angelo Scuteri
  59. Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.

    • James Scott &
    • Jaspal S. Kooner
  60. Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.

    • David Schlessinger &
    • Edward G. Lakatta
  61. Department of Health Research and Policy, Stanford University, Stanford, California 94305, USA.

    • Chiara Sabatti
  62. Department of Clinical Chemistry, University of Oulu, FI-90220 Oulu, Finland.

    • Aimo Ruokonen
  63. The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa, Ottawa K1Y 4W7, Canada.

    • Robert Roberts &
    • Ruth McPherson
  64. Departments of Medicine, Epidemiology, and Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.

    • Bruce M. Psaty
  65. Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso 1, 39100 Bolzano, Italy – affiliated institute of the University of Lübeck, Germany.

    • Peter P. Pramstaller,
    • Irene Pichler,
    • Cristian Pattaro &
    • Andrew A. Hicks
  66. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden.

    • Nancy L. Pedersen,
    • Patrik K. E. Magnusson &
    • Erik Ingelsson
  67. Amgen, Thousand Oaks, California 91320, USA.

    • Alex N. Parker
  68. Genetic and Molecular Epidemiology Laboratory, McMaster University, Hamilton, Ontario L8N3Z5, Canada.

    • Guillaume Pare
  69. Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.

    • Ben A. Oostra
  70. Institut fur Humangenetik, Helmholtz Zentrum Munchen, Deutsches Forschungszentrum fur Umwelt und Gesundheit, 85764 Neuherberg, Germany.

    • Thomas Meitinger
  71. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675 Muenchen, Germany.

    • Thomas Meitinger
  72. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Mark I. McCarthy
  73. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Mark I. McCarthy
  74. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Mark I. McCarthy
  75. Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol BS8 2BN, UK.

    • Wendy McArdle
  76. Institute of Applied Genomics, via Linussio 51, 33100 Udine, Italy.

    • Fabio Marroni
  77. Cardiovascular Epidemiology and Genetics, Institut Municipal d’Investigacio Medica, 08003 Barcelona, Spain.

    • Gavin Lucas
  78. Transplantation Laboratory, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland.

    • Marja-Liisa Lokki
  79. Montreal Heart Institute (Research Center), Université de Montréal, Montréal, Québec H1T 1C8, Canada.

    • Guillaume Lettre
  80. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Lenore J. Launer &
    • Tamara B. Harris
  81. Science Center, Tampere University Hospital, FI-33521 Tampere, Finland.

    • Reijo Laaksonen
  82. Institute of Regional Health Research and the Danish Twin Registry, Institute of Public Health, University of Southern Denmark, JBWinsløws Vej 9B, DK-5000, Odense, Denmark.

    • Kirsten O. Kyvik
  83. Faculty of Medicine, Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland.

    • Jaakko Kaprio
  84. Massachusetts General Hospital Weight Center, Boston, Massachusetts 02114, USA.

    • Lee M. Kaplan
  85. Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, SE-75185 Uppsala, Sweden.

    • Åsa Johansson,
    • Wilmar Igl &
    • Ulf Gyllensten
  86. Department of Epidemiology & Biostatistics, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK.

    • Marjo-Riitta Jarvelin &
    • Paul Elliott
  87. Department of Public Health Science and General Practice, University of Oulu, FI-90220 Oulu, Finland.

    • Marjo-Riitta Jarvelin
  88. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany.

    • Christian Hengstenberg
  89. Department of Epidemiology and Preventive Medicine Regensburg University Medical Center Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.

    • Iris M. Heid
  90. Department of Biomedical Engineering and Computational Science, Aalto University School of Science and Technology, FI-00076 Aalto, Finland.

    • Aki S. Havulinna
  91. LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.

    • Alistair S. Hall
  92. Department of Medicine, Helsinki University Hospital, FI-00029 Helsinki, Finland.

    • Leif C. Groop
  93. Department of Psychiatry, Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.

    • Nelson B. Freimer
  94. Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.

    • Luigi Ferrucci
  95. Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany.

    • Jeanette Erdmann &
    • Heribert Schunkert
  96. MRC-HPA Centre for Environment and Health, Imperial College London, London W2 1PG, UK.

    • Paul Elliott
  97. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.

    • Anna F. Dominiczak
  98. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.

    • Ulf de Faire
  99. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Francis S. Collins &
    • Lori L. Bonnycastle
  100. Departments of Vascular Medicine & Cardiology, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands.

    • S. Matthijs Boekholdt
  101. Department of Physiology and Biophysics, University of Southern California, Los Angeles, California 90033, USA.

    • Richard N. Bergman
  102. Geriatric Unit, Azienda Sanitaria Firenze (ASF), 50125 Florence, Italy.

    • Stefania Bandinelli
  103. Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Christie M. Ballantyne
  104. Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Themistocles L. Assimes &
    • Thomas Quertermous
  105. Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Republic of Singapore.

    • Tien Y. Wong
  106. Departments of Medicine/Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.

    • E-Shyong Tai
  107. Office of Population Studies Foundation, University of San Carlos, Cebu City 6000, Philippines.

    • Alan B. Feranil
  108. Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.

    • Christopher W. Kuzawa
  109. Department of Nutrition, Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina 27516, USA.

    • Linda S. Adair
  110. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39126, USA.

    • Herman A. Taylor Jr &
    • James G. Wilson
  111. Children’s Hospital Oakland Research Institute, Oakland, California 94609, USA.

    • Ronald M. Krauss
  112. Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.

    • Jose M. Ordovas
  113. Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.

    • Jose M. Ordovas
  114. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

    • Patricia B. Munroe
  115. Sage Bionetworks, Seattle, Washington 98109, USA.

    • Eric E. Schadt
  116. Division of Community Health Sciences, St George’s University of London, London SW17 0RE, UK.

    • David P. Strachan
  117. Department of Cardiovascular Sciences, University of Leicester, NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK.

    • Nilesh J Samani
  118. Deceased.

    • Leena Peltonen

Contributions

T.M.T., K.M., A.V.S., A.C.E., I.M.S., M.K. and J.P.P. carried out the primary data analyses and/or experimental work. All other authors contributed to additional analyses. L.A.C., M.S.S., P.M.R., D.J.R., C.M.v.D., L.P., G.R.A., M.B. and S.K. conceived, designed, and supervised the study. K.M. wrote the manuscript.

Competing financial interests

Competing interests: D.M.W., K.S. and V.M. are full-time employees of GlaxoSmithKline. M.S.S. has received research funding from GlaxoSmithKline. P.V. and G.W. received grant money from GlaxoSmithKline to fund the CoLaus study. G.T., K.S., U.T. and H.H. are full-time employees of deCODE genetics. The other authors declare no competing financial interests.

Corresponding author

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Supplementary information

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  1. Supplementary Information (2.8M)

    This file contains Supplementary Methods, References, Supplementary Figures 1-3 with legends, Supplementary Tables 1-19 and a full list of Acknowledgments.

Additional data