Letter | Published:

Common variants associated with plasma triglycerides and risk for coronary artery disease

Nature Genetics volume 45, pages 13451352 (2013) | Download Citation

Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10−8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

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Acknowledgements

We thank the Global Lipids Genetics Consortium for early access to the association results of the Metabochip study. S. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Howard Goodman Fellowship from Massachusetts General Hospital, the Donovan Family Foundation, R01HL107816 from the US National Institutes of Health and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. G.P. is supported by award T32HL007208 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the US National Institutes of Health.

Author information

Author notes

    • Mark J Daly
    • , Benjamin M Neale
    •  & Sekar Kathiresan

    These authors jointly directed this work. Correspondence should be addressed to S. Kathiresan (skathiresan@partners.org), B.M.N. (bneale@broadinstitute.org) or M.J.D. (mjdaly@atgu.mgh.harvard.edu).

    • Mark J Daly
    • , Benjamin M Neale
    •  & Sekar Kathiresan

    These author contributed equally to this work.

Affiliations

  1. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Ron Do
    • , Chi Gao
    •  & Sekar Kathiresan
  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Ron Do
    • , Chi Gao
    • , Gina M Peloso
    • , Richa Saxena
    • , David Altshuler
    • , Mark J Daly
    • , Benjamin M Neale
    •  & Sekar Kathiresan
  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Ron Do
    • , David Altshuler
    •  & Sekar Kathiresan
  4. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Ron Do
    • , Chi Gao
    • , Gina M Peloso
    • , Tõnu Esko
    • , Pierre Fontanillas
    • , Cameron D Palmer
    • , Sailaja Vedantam
    • , Joel N Hirschhorn
    • , David Altshuler
    • , Mark J Daly
    • , Benjamin M Neale
    •  & Sekar Kathiresan
  5. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Cristen J Willer
  6. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

    • Cristen J Willer
    •  & Ellen M Schmidt
  7. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Cristen J Willer
  8. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Cristen J Willer
    • , Sebanti Sengupta
    • , Jin Chen
    • , Jennifer L Bragg-Gresham
    • , Anne U Jackson
    • , Carlo Sidore
    • , Tanya M Teslovich
    • , Michael Boehnke
    •  & Goncalo R Abecasis
  9. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Gina M Peloso
    •  & L Adrienne Cupples
  10. Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.

    • Stefan Gustafsson
    • , Andrea Ganna
    • , Ci Song
    • , Agneta Siegbahn
    •  & Erik Ingelsson
  11. Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Stefan Gustafsson
    • , Andrea Ganna
    • , Ci Song
    •  & Erik Ingelsson
  12. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Stavroula Kanoni
    • , Deepti Gurdasani
    • , Inês Barroso
    • , Theodore Papamarkou
    • , Cristina Pomilla
    • , Kathleen Stirrups
    • , Nicholas Wainwright
    • , Elizabeth H Young
    • , Samuli Ripatti
    • , Manjinder S Sandhu
    •  & Panos Deloukas
  13. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Andrea Ganna
    • , Patrik K E Magnusson
    • , Ci Song
    •  & Nancy L Pedersen
  14. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Martin L Buchkovich
    • , Ying Wu
    •  & Karen L Mohlke
  15. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Samia Mora
    • , Paul M Ridker
    •  & Daniel I Chasman
  16. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Samia Mora
    • , Paul M Ridker
    •  & Daniel I Chasman
  17. Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.

    • Jacques S Beckmann
  18. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Jacques S Beckmann
  19. Division of Preventive Medicine and Health Services Research, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

    • Hsing-Yi Chang
  20. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Ayşe Demirkan
    • , Aaron Isaacs
    •  & Cornelia M van Duijn
  21. Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Heleen M Den Hertog
    • , Evita G Van den Herik
    •  & Peter J Koudstaal
  22. Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School. Dundee, UK.

    • Louise A Donnelly
    • , Alex S F Doney
    • , Andrew D Morris
    •  & Colin N A Palmer
  23. Cardiology, Department of Specialities of Medicine, Geneva University Hospital, Geneva, Switzerland.

    • Georg B Ehret
    •  & François Mach
  24. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Georg B Ehret
    •  & Aravinda Chakravarti
  25. Estonian Genome Center of the University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Krista Fischer
    • , Evelin Mihailov
    • , Markus Perola
    •  & Andres Metspalu
  26. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Evelin Mihailov
    •  & Andres Metspalu
  27. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Mary F Feitosa
    •  & Ingrid B Borecki
  28. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Teresa Ferreira
    • , Cecilia M Lindgren
    • , Mark I McCarthy
    •  & Erik Ingelsson
  29. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Ross M Fraser
    • , Jennifer L Bolton
    • , Igor Rudan
    • , Sarah H Wild
    • , James F Wilson
    • , Harry Campbell
    •  & Jackie F Price
  30. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Daniel F Freitag
    • , Deepti Gurdasani
    • , Theodore Papamarkou
    • , Cristina Pomilla
    • , Nicholas Wainwright
    • , Elizabeth H Young
    • , John Danesh
    • , Danish Saleheen
    •  & Manjinder S Sandhu
  31. Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Kauko Heikkilä
    •  & Jaakko Kaprio
  32. Centre For Paediatric Epidemiology and Biostatistics/Medical Research Council (MRC) Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, UK.

    • Elina Hyppönen
    •  & Chris Power
  33. Centre for Medical Systems Biology, Leiden, The Netherlands.

    • Aaron Isaacs
    •  & Cornelia M van Duijn
  34. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

    • Åsa Johansson
    •  & Ulf Gyllensten
  35. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

    • Åsa Johansson
    • , Agneta Siegbahn
    •  & Lars Wallentin
  36. Genome Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Toby Johnson
    •  & Patricia B Munroe
  37. Clinical Pharmacology, National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit, 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
  38. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    •  & Marjo-Riitta Järvelin
  39. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    • , Paul Elliott
    •  & Marjo-Riitta Järvelin
  40. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Johannes Kettunen
    • , Markus Perola
    • , Ida Surakka
    • , Aarno Palotie
    • , Kaisa Silander
    • , Jaakko Kaprio
    •  & Samuli Ripatti
  41. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Johannes Kettunen
    • , Markus Perola
    • , Ida Surakka
    • , Kaisa Silander
    •  & Samuli Ripatti
  42. Department of Internal Medicine II–Cardiology, University of Ulm Medical Centre, Ulm, Germany.

    • Marcus E Kleber
  43. Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.

    • Marcus E Kleber
    •  & Winfried März
  44. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Xiaohui Li
    • , Eric Kim
    •  & Jerome I Rotter
  45. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Jian'an Luan
    • , Claudia Langenberg
    • , Ruth J F Loos
    • , Ken K Ong
    • , Jing Hua Zhao
    •  & Nicholas J Wareham
  46. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  47. Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  48. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Massimo Mangino
    •  & Tim D Spector
  49. Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland, School of Medicine, Baltimore, Maryland, USA.

    • May E Montasser
    • , Jeffrey R O'Connell
    • , Braxton D Mitchell
    •  & Alan R Shuldiner
  50. Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

    • Martina Müller-Nurasyid
    • , Ann-Kristin Petersen
    •  & Christian Gieger
  51. Department of Medicine I, University Hospital Grosshadern, Ludwig Maximilians University of Munich, Munich, Germany.

    • Martina Müller-Nurasyid
  52. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University of Munich, Munich, Germany.

    • Martina Müller-Nurasyid
  53. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Ilja M Nolte
  54. Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA.

    • Cameron D Palmer
    • , Sailaja Vedantam
    •  & Joel N Hirschhorn
  55. Division of Genetics, Program in Genomics, Children's Hospital Boston, Boston, Massachusetts, USA.

    • Cameron D Palmer
    • , Sailaja Vedantam
    •  & Joel N Hirschhorn
  56. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.

    • Serena Sanna
    •  & Carlo Sidore
  57. Center for Neurobehavioral Genetics, The Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.

    • Susan K Service
    •  & Nelson B Freimer
  58. Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK.

    • Sonia Shah
    • , Meena Kumari
    • , Aroon Hingorani
    •  & Mika Kivimaki
  59. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Scania University Hospital, Malmö, Sweden.

    • Dmitry Shungin
    •  & Paul W Franks
  60. Department of Odontology, Umeå University, Umeå, Sweden.

    • Dmitry Shungin
  61. Department of Public Health and Primary Care, Unit of Medicine, Umeå University, Umeå, Sweden.

    • Dmitry Shungin
    •  & Paul W Franks
  62. Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.

    • Carlo Sidore
  63. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

    • Rona J Strawbridge
    •  & Anders Hamsten
  64. Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

    • Rona J Strawbridge
    •  & Anders Hamsten
  65. Clinical Research Branch, US National Institutes of Health, Baltimore, Maryland, USA.

    • Toshiko Tanaka
    •  & Luigi Ferrucci
  66. deCODE Genetics/Amgen, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Hilma Holm
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  67. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  68. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  69. Human Genetics Center, University of Texas Health Science Center, School of Public Health, Houston, Texas, USA.

    • Kelly A Volcik
    •  & Eric Boerwinkle
  70. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

    • Lindsay L Waite
    •  & Devin Absher
  71. MRC Unit for Lifelong Health and Ageing, London, UK.

    • Andrew Wong
    • , Ken K Ong
    •  & Diana Kuh
  72. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Weihua Zhang
    • , Paul Elliott
    • , John C Chambers
    •  & Marjo-Riitta Järvelin
  73. Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.

    • Weihua Zhang
    • , John C Chambers
    •  & Jaspal S Kooner
  74. Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda.

    • Gershim Asiki
    • , Pontiano Kaleebu
    • , Rebecca N Nsubuga
    •  & Janet Seeley
  75. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Inês Barroso
  76. NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Inês Barroso
  77. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Latonya F Been
    • , Martha L Gravito
    •  & Dharambir K Sanghera
  78. Genome Technology Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Lori L Bonnycastle
    • , Narisu Narisu
    • , Amy J Swift
    •  & Francis S Collins
  79. Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy.

    • Paolo Brambilla
  80. MedStar Health Research Institute, Hyattsville, Maryland, USA.

    • Mary S Burnett
    •  & Stephen E Epstein
  81. Research Centre on Public Health, University of Milano-Bicocca, Monza, Italy.

    • Giancarlo Cesana
  82. Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.

    • Maria Dimitriou
    •  & George Dedoussis
  83. Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg, Germany.

    • Angela Döring
    •  & Christa Meisinger
  84. Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.

    • Angela Döring
  85. MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Paul Elliott
    •  & Marjo-Riitta Järvelin
  86. The Laboratory in Mjodd, Reykjavik, Iceland.

    • Gudmundur Ingi Eyjolfsson
  87. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Bruna Gigante
    •  & Ulf de Faire
  88. Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Mark O Goodarzi
    •  & Michelle R Jones
  89. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

    • Harald Grallert
    • , Thomas Illig
    •  & Norman Klopp
  90. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Christopher J Groves
    •  & Mark I McCarthy
  91. Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden.

    • Göran Hallmans
  92. Department of Clinical Sciences/Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Anneli Pouta
  93. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

    • Caroline Hayward
  94. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

    • Dena Hernandez
  95. Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck).

    • Andrew A Hicks
    •  & Peter P Pramstaller
  96. Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

    • Yi-Jen Hung
  97. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.

    • Thomas Illig
    •  & Norman Klopp
  98. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.

    • John J P Kastelein
    •  & G Kees Hovingh
  99. Clinical Gerontology Unit, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  100. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

    • Pirjo Komulainen
    • , Timo A Lakka
    •  & Rainer Rauramaa
  101. Department of Internal Medicine, Division of Endocrine and Metabolism, Taichung Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

    • Shih-Yi Lin
  102. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaana Lindström
    •  & Jaakko Tuomilehto
  103. The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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  104. The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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    • Daniel J Rader
    •  & Muredach P Reilly
  118. Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Translational Research Center, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
    •  & Muredach P Reilly
  119. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    • , Andre G Uitterlinden
    •  & Albert Hofman
  120. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    •  & Andre G Uitterlinden
  121. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.

    • Fernando Rivadeneira
    • , Andre G Uitterlinden
    •  & Albert Hofman
  122. Department of Clinical Sciences/Clinical Chemistry, University of Oulu, Oulu, Finland.

    • Aimo Ruokonen
  123. National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Nilesh Samani
  124. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Nilesh Samani
  125. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

    • Hubert Scharnagl
    •  & Winfried März
  126. School of International Development, University of East Anglia, Norwich, UK.

    • Janet Seeley
  127. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Alena Stančáková
  128. INSERM UMRS 937, Pierre and Marie Curie University, Paris, France.

    • Laurence Tiret
  129. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • L Joost van Pelt
  130. LifeLines Cohort Study, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • L Joost van Pelt
    • , Cisca Wijmenga
    •  & Bruce H R Wolffenbuttel
  131. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Cisca Wijmenga
  132. Department of Biological Psychology, VU University, Amsterdam, The Netherlands.

    • Gonneke Willemsen
    •  & Dorret I Boomsma
  133. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.

    • Tom Wilsgaard
    •  & Inger Njølstad
  134. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Linda S Adair
  135. Department of Epidemiology and Public Health, University of Strasbourg, Faculty of Medicine, Strasbourg, France.

    • Dominique Arveiler
  136. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Themistocles L Assimes
    •  & Thomas Quertermous
  137. Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.

    • Stefania Bandinelli
  138. Chemical Pathology, Department of Pathology, University of the West Indies, Mona, Jamaica.

    • Franklyn Bennett
  139. Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland.

    • Murielle Bochud
    •  & Pascal Bovet
  140. Department of Internal Medicine, Division of Endocrinology and Diabetes, Ulm University Medical Centre, Ulm, Germany.

    • Bernhard O Boehm
  141. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

    • Bernhard O Boehm
  142. Department of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.

    • Stefan R Bornstein
    •  & Peter E H Schwarz
  143. Ministry of Health, Victoria, Republic of Seychelles.

    • Pascal Bovet
  144. Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland.

    • Michel Burnier
  145. Imperial College Healthcare National Health Service (NHS) Trust, London, UK.

    • John C Chambers
    •  & Jaspal S Kooner
  146. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Yii-Der Ida Chen
  147. Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Yii-Der Ida Chen
  148. Department of Preventive Medicine and Epidemiology, Loyola University Medical School, Maywood, Illinois, USA.

    • Richard S Cooper
    •  & Bamidele O Tayo
  149. Office of Population Studies Foundation, University of San Carlos, Talamban, Cebu City, Philippines.

    • Alan B Feranil
  150. Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France.

    • Jean Ferrières
  151. Department of Psychiatry, University of California, Los Angeles, Los Angeles, California, USA.

    • Nelson B Freimer
  152. Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Leif C Groop
  153. Department of Medicine, Helsinki University Hospital, Helsinki, Finland.

    • Leif C Groop
  154. Icelandic Heart Association, Kopavogur, Iceland.

    • Vilmundur Gudnason
  155. Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

    • Anders Hamsten
  156. Laboratory of Epidemiology, Demography and Biometry, National Institute on Ageing, Bethesda, Maryland, USA.

    • Tamara B Harris
  157. Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

    • Chao Agnes Hsiung
  158. Cardiovascular Genetics, British Heart Foundation Laboratories, Institute Cardiovascular Science, University College London, London, UK.

    • Steve E Humphries
  159. Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Steven C Hunt
  160. Nord-Trøndelag Health Study (HUNT) Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.

    • Kristian Hveem
  161. Kaiser Permanente, Division of Research, Oakland, California, USA.

    • Carlos Iribarren
  162. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Marjo-Riitta Järvelin
  163. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland.

    • Antti Jula
  164. Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.

    • Mika Kähönen
  165. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
  166. Institute of Clinical Medicine, Department of Medicine, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland.

    • Antero Kesäniemi
  167. National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

    • Jaspal S Kooner
  168. Children's Hospital Oakland Research Institute, Oakland, California, USA.

    • Ronald M Krauss
  169. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  170. Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.

    • Kirsten O Kyvik
  171. Odense Patient Data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark.

    • Kirsten O Kyvik
  172. Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.

    • Timo A Lakka
  173. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Lars Lind
    • , Agneta Siegbahn
    •  & Lars Wallentin
  174. Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland, Australia.

    • Nicholas G Martin
    •  & John B Whitfield
  175. Synlab Academy, Synlab Services, Mannheim, Germany.

    • Winfried März
  176. Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Jamaica.

    • Colin A McKenzie
  177. INSERM U872, Centre de Recherche des Cordeliers, Paris, France.

    • Pierre Meneton
  178. Department of Medicine, Kuopio University Hospital, Kuopio, Finland.

    • Leena Moilanen
  179. Department of Neurology, General Central Hospital, Bolzano, Italy.

    • Peter P Pramstaller
  180. Department of Neurology, University of Lübeck, Lübeck, Germany.

    • Peter P Pramstaller
  181. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  182. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Bruce M Psaty
  183. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.

    • Rainer Rauramaa
  184. Center for Non-Communicable Diseases, Karachi, Pakistan.

    • Danish Saleheen
  185. Department of Medicine, University of Pennsylvania, USA.

    • Danish Saleheen
  186. Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Veikko Salomaa
  187. South Karelia Central Hospital, Lappeenranta, Finland.

    • Jouko Saramies
  188. Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany.

    • Peter E H Schwarz
  189. Department of Internal Medicine, Division of Endocrine and Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Wayne H-H Sheu
  190. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  191. Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

    • Kari Stefansson
    •  & Unnur Thorsteinsdottir
  192. Division of Population Health Sciences and Education, St. George's, University of London, London, UK.

    • David P Strachan
  193. Department of Pharmacological Sciences, University of Milan, Monzino Cardiology Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

    • Elena Tremoli
  194. Centre for Vascular Prevention, Danube University Krems, Krems, Austria.

    • Jaakko Tuomilehto
  195. King Abdulaziz University, Faculty of Medicine, Jeddah, Saudi Arabia.

    • Jaakko Tuomilehto
  196. Red La Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (RECAVA) Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain.

    • Jaakko Tuomilehto
  197. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

    • Matti Uusitupa
  198. Research Unit, Kuopio University Hospital, Kuopio, Finland.

    • Matti Uusitupa
  199. Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.

    • Peter Vollenweider
  200. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Bruce H R Wolffenbuttel
  201. Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain.

    • Jose M Ordovas
  202. Madrid Institute for Advanced Studies (Instituto Madrileño de Estudios Avanzados)–Alimentación, Madrid, Spain.

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

    • Jose M Ordovas
  204. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Paul W Franks
  205. Framingham Heart Study, Framingham, Massachusetts, USA.

    • L Adrienne Cupples
  206. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Stephen S Rich
    •  & Benjamin M Neale
  207. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Mark J Daly

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Contributions

R.D. carried out primary data analyses and prepared the supplementary information. R.D. and C. Gao prepared figures and tables. C.J.W., E.M.S., S. Sengupta, S.S.R. and G.R.A. contributed meta-analysis results. J.C. and M.L.B. performed bioinformatic analyses. R.D., M.J.D., B.M.N. and S. Kathiresan contributed to the design and conduct of the study. R.D., M.J.D., B.M.N. and S. Kathiresan wrote the manuscript.

All authors contributed to the research and reviewed the manuscript.

Design, management and coordination of contributing cohorts: (ADVANCE) T.L.A.; (AGES Reykjavik study) T.B.H. and V.G.; (AIDHS/SDS) D.K.S.; (AMC-PAS) P.D. and G.K.H.; (Amish GLGC) A.R.S.; (ARIC) E.B.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (B58C-Metabochip) C.M.L., C. Power and M.I.M.; (BLSA) L.F.; (BRIGHT) P.B.M.; (CARDIoGRAM) N.S.; (CHS) B.M.P. and J.I.R.; (CLHNS) A.B.F., K.L.M. and L.S.A.; (CoLaus) P.V.; (CROATIA-Vis) C.H. and I.R.; (deCODE) K. Stefansson and U.T.; (DIAGEN) P.E.H.S. and S.R.B.; (DILGOM) S.R.; (DPS) M.U.; (DR's EXTRA) R.R.; (EAS) J.F.P.; (EGCUT (Estonian Genome Center of the University of Tartu)) A.M.; (ELY) N.J.W.; (ENGAGE) N.B.F.; (EPIC) N.W. and K.-T.K.; (EPIC_N_OBSET GWAS) E.H.Y.; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) P.J.K.; (Family Heart Study (FHS)) I.B.B.; (FBPP) A.C., R.S.C. and S.C.H.; (FENLAND) R.J.F.L. and N.W.; (FIN-D2D 2007) A.K. and L.M.; (FINCAVAS) M. Kähönen; (Framingham) L.A.C., S. Kathiresan and J.M.O.; (FRISCII) A. Siegbahn and L.W.; (FUSION GWAS) K.L.M. and M. Boehnke; (FUSION stage 2) F.S.C., J.T. and J. Saramies; (GenomEUTwin) J.B.W., N.G.M., K.O.K., V.S., J. Kaprio, A. Jula, D.I.B., N.L.P. and T.D.S.; (GLACIER) P.W.F. and G.H.; (Go-DARTS) A.D.M. and C.N.A.P.; (GxE/Spanish Town) B.O.T., C.A.M., F.B., J.N.H. and R.S.C.; (HUNT2) K. Hveem; (IMPROVE) U.d.F., A. Hamsten, E.T. and S.E.H.; (InCHIANTI) S.B.; (KORAF4) C. Gieger; (LifeLines) B.H.R.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) B.O.B. and W.M.; (MDC) L.C.G., D. Altshuler and S. Kathiresan; (MEDSTAR) M.S.B. and S.E.E.; (METSIM) J. Kuusisto and M.L.; (MICROS) P.P.P.; (MORGAM) D. Arveiler and J.F.; (MRC/UVRI GPC GWAS) P. Kaleebu, G.A., J. Seeley and E.H.Y.; (MRC National Survey of Health and Development) D.K.; (NFBC1986) M.-R.J.; (NSPHS) U.G.; (ORCADES) H.C.; (PARC) Y.-D.I.C., R.M.K. and J.I.R.; (PennCath) D.J.R. and M.P.R.; (PIVUS) E.I. and L.L.; (PROMIS) J.D., P.D. and D. Saleheen; (Rotterdam Study) A. Hofman and A.G.U.; (SardiNIA) G.R.A.; (SCARFSHEEP) A. Hamsten and U.d.F.; (SEYCHELLES) M. Burnier, M. Bochud and P. Bovet; (SUVIMAX) P.M.; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) T.L.A., Y.-D.I.C., C.A.H., T.Q., J.I.R. and W.H.-H.S.; (THISEAS) G.D. and P.D.; (Tromsø) I.N.; (TWINGENE) U.d.F. and E.I.; (ULSAM) E.I.; and (Whitehall II) A. Hingorani and M. Kivimaki.

Genotyping of contributing cohorts: (ADVANCE) D. Absher; (AIDHS/SDS) L.F.B. and M.L.G.; (AMC-PAS) P.D. and G.K.H.; (B58C-WTCCC and B58C-T1DGC) W.L.M.; (B58C-Metabochip) M.I.M.; (BLSA) D.H.; (BRIGHT) P.B.M.; (CHS) J.I.R.; (DIAGEN) N.N. and G.M.; (DILGOM) A. Palotie; (DR's EXTRA) T.A.L.; (EAS) J.F.W.; (EGCUT (Estonian Genome Center of the University of Tartu)) T.E.; (EPIC) P.D.; (EPIC_N_SUBCOH GWAS) I.B.; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) C.M.v.D.; (FBPP) A.C. and G.B.E.; (FENLAND) M.S.S.; (FIN-D2D 2007) A.J.S.; (FINCAVAS) T.L.; (Framingham) J.M.O.; (FUSION stage 2) L.L.B.; (GLACIER) I.B.; (Go-DARTS) C.J.G., C.N.A.P. and M.I.M.; (IMPROVE) A. Hamsten; (KORAF3) H.G. and T.I.; (KORAF4) N.K.; (LifeLines) C.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) M.E.K.; (MDC) B.F.V. and R.D.; (MICROS) A.A.H.; (MORGAM) L.T. and P. Brambilla; (MRC/UVRI GPC GWAS) M.S.S.; (MRC National Survey of Health and Development) A.W., D.K. and K.K.O.; (NFBC1986) A.-L.H., M.-R.J., M.I.M., P.E. and S.V.; (NSPHS and FRISCII) Å. Johansson; (ORCADES) H.C.; (PARC) M.O.G., M.R.J. and J.I.R.; (PIVUS) E.I. and L.L.; (PROMIS) P.D. and K. Stirrups; (Rotterdam Study) A.G.U. and F.R.; (SardiNIA) R.N.; (SCARFSHEEP) B.G. and R.J.S.; (SEYCHELLES) F.M. and G.B.E.; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) D. Absher, T.L.A., E.K., T.Q. and L.L.W.; (THISEAS) P.D.; (TWINGENE) A. Hamsten and E.I.; (ULSAM) E.I.; (WGHS) S.M., D.I.C. and P.M.R.; and (Whitehall II) A. Hingorani, C.L., M. Kumari and M. Kivimaki.

Phenotype definition of contributing cohorts: (ADVANCE) C.I.; (AGES Reykjavik study) T.B.H. and V.G.; (AIDHS/SDS) L.F.B.; (AMC-PAS) J.J.P.K.; (Amish GLGC) A.R.S. and B.D.M.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (B58C-Metabochip) C. Power and E.H.; (BRIGHT) P.B.M.; (CHS) B.M.P.; (CoLaus) P.V.; (deCODE) G.I.E., H.H. and I.O.; (DIAGEN) G.M.; (DILGOM) K. Silander; (DPS) J. Lindström; (DR's EXTRA) P. Komulainen; (EAS) J.L.B.; (EGCUT (Estonian Genome Center of the University of Tartu)) A.M.; (EGCUT (Estonian Genome Center of the University of Tartu)) K.F.; (ERF and Rotterdam Study) A. Hofman; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) E.G.V.d.H., H.M.D.H. and P.J.K.; (FBPP) A.C., R.S.C. and S.C.H.; (FINCAVAS) T.V.M.N.; (Framingham) S. Kathiresan and J.M.O.; (GenomEUTwin: MZGWA) J.B.W.; (GenomEUTwin-FINRISK) V.S.; (GenomEUTwin-FINTWIN) J. Kaprio and K. Heikkilä; (GenomEUTwin-GENMETS) A. Jula; (GenomEUTwin-NLDTWIN) G.W.; (Go-DARTS) A.S.F.D., A.D.M., C.N.A.P. and L.A.D.; (GxE/Spanish Town) C.A.M. and F.B.; (IMPROVE) U.d.F., A. Hamsten and E.T.; (KORAF3) C.M.; (KORAF4) A. Döring; (LifeLines) L.J.v.P.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) H.S.; (MDC) L.C.G.; (METSIM) A. Stančáková; (MORGAM) G.C.; (MRC/UVRI GPC GWAS) R.N.N.; (MRC National Survey of Health and Development) D.K.; (NFBC1986) A.R., A.-L.H., A. Pouta and M.-R.J.; (NSPHS and FRISCII) Å. Johansson; (NSPHS) U.G.; (ORCADES) S.H.W.; (PARC) Y.-D.I.C. and R.M.K.; (PIVUS) E.I. and L.L.; (PROMIS) D.F.F.; (Rotterdam Study) A. Hofman; (SCARFSHEEP) U.d.F. and B.G.; (SEYCHELLES) M. Burnier, M. Bochud and P. Bovet; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) H.-Y.C., C.A.H., Y.-J.H., E.K., S.-Y.L. and W.H.-H.S.; (THISEAS) G.D. and M.D.; (Tromsø) T.W.; (TWINGENE) U.d.F. and E.I.; (ULSAM) E.I.; (WGHS) P.M.R.; and (Whitehall II) M. Kumari.

Primary analysis from contributing cohorts: (ADVANCE) L.L.W.; (AIDHS/SDS) R.S.; (AMC-PAS) S. Kanoni; (Amish GLGC) J.R.O. and M.E.M.; (ARIC) K.A.V.; (B58C-Metabochip) C.M.L., E.H. and T.F.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (BLSA) T.T.; (BRIGHT) T.J.; (CLHNS) Y.W.; (CoLaus) J.S.B.; (deCODE) G.T.; (DIAGEN) A.U.J.; (DILGOM) M.P.; (EAS) R.M.F.; (DPS) A.U.J.; (DR'S EXTRA) A.U.J.; (EGCUT (Estonian Genome Center of the University of Tartu)) E.M., K.F. and T.E.; (ELY) D.G.; (EPIC) K. Stirrups and D.G.; (EPIC_N_OBSET GWAS) E.H.Y. and C.L.; (EPIC_N_SUBCOH GWAS) N.W.; (ERF) A.I.; (ESS (Erasmus Stroke Study)) C.M.v.D. and E.G.V.d.H.; (EUROSPAN) A. Demirkan; (Family Heart Study (FHS)) I.B.B. and M.F.F.; (FBPP) A.C. and G.B.E.; (FENLAND) T.P. and C. Pomilla; (FENLAND GWAS) J.H.Z. and J. Luan; (FIN-D2D 2007) A.U.J.; (FINCAVAS) L.-P.L.; (Framingham) L.A.C. and G.M.P.; (FRISCII and NSPHS) Å. Johansson; (FUSION stage 2) T.M.T.; (GenomEUTwin-FINRISK) J. Kettunen; (GenomEUTwin-FINTWIN) K. Heikkilä; (GenomEUTwin-GENMETS) I.S.; (GenomEUTwin-SWETWIN) P.K.E.M.; (GenomEUTwin-UK-TWINS) M.M.; (GLACIER) D. Shungin; (GLACIER) P.W.F.; (Go-DARTS) C.N.A.P. and L.A.D.; (GxE/Spanish Town) C.D.P.; (HUNT) A.U.J.; (IMPROVE) R.J.S.; (InCHIANTI) T.T.; (KORAF3) M.M.-N.; (KORAF4) A.-K.P.; (LifeLines) I.M.N.; (LOLIPOP) W.Z.; (LURIC) M.E.K.; (MDC) B.F.V.; (MDC) P.F. and R.D.; (METSIM) A.U.J.; (MRC/UVRI GPC GWAS) R.N.N.; (MRC National Survey of Health and Development) A.W. and J. Luan; (NFBC1986) M. Kaakinen, I.S. and S.K.S.; (NSPHS and FRISCII) Å. Johansson; (PARC) X.L.; (PIVUS) C. Song and E.I.; (PROMIS) J.D., D.F.F. and K. Stirrups; (Rotterdam Study) A.I.; (SardiNIA) C. Sidore, J.L.B.-G. and S. Sanna; (SCARFSHEEP) R.J.S.; (SEYCHELLES) G.B.E. and M. Bochud; (SUVIMAX) T.J.; (Swedish Twin Registry) C. Song and E.I.; (TAICHI) D. Absher, T.L.A., H.-Y.C., M.O.G., C.A.H., T.Q. and L.L.W.; (THISEAS) S. Kanoni; (Tromsø) A.U.J.; (TWINGENE) A.G. and E.I.; (ULSAM) C. Song, E.I. and S.G.; (WGHS) D.I.C.; and (Whitehall II) S. Shah.

Competing interests

B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll), and he serves on the Steering Committee of the Yale Open-Data Project funded by the Medtronic. P.V. received an unrestricted grant from GlaxoSmithKline to build the CoLaus study. G.T., H.H., A.K., K. Stefansson and U.T. are employees of deCODE Genetics/Amgen, a biotechnology company. I.B. and spouse own stock in GlaxoSmithKline and Incyte, Ltd. S. Kathiresan serves on scientific advisory boards for Merck, Celera, American Genomics and Catabasis. He has received unrestricted research grants from Merck and Pfizer.

Corresponding authors

Correspondence to Mark J Daly or Benjamin M Neale or Sekar Kathiresan.

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https://doi.org/10.1038/ng.2795

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