Letter | Published:

Exome-wide association study of plasma lipids in >300,000 individuals

Nature Genetics volume 49, pages 17581766 (2017) | Download Citation

Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

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Acknowledgements

D.J.L. is partially supported by R01HG008983 from the National Human Genome Research Institute of the National Institute of Health, and R21DA040177 and R01DA037904 from the National Institute of Drug Abuse of the National Institute of Health. G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health award K01HL125751. A.P.P. is supported by a research fellowship from the Stanley J. Sarnoff Cardiovascular Research Foundation. H. Tada is supported by a grant from the Japanese Circulation Society to study in the United States. The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F. E.K.S. is supported by NIH grants R01 DK106621 and R01 DK107904, the University of Michigan Biological Sciences Scholars Program, and the University of Michigan Department of Internal Medicine. T.D.S. is supported by an ERC Advanced Principal Investigator award. A.P.M. is supported as a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant no. WT098017). Y.E.C. is supported by HL117491 and HL129778 from the NIH. S.K.G. is supported by HL122684 from the NIH. P.L.A. is supported by NHLBI R21 HL121422-02 from the NIH. C.L., N.J.W., and R.A.S. acknowledge funding from the Medical Research Council, UK (MC_UU_12015/1). J.D. is supported as a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. C.J.W. is supported by HL094535 and HL109946 from the NIH. S. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564 and R33 HL120781 from the NIH.

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health or the US Department of Health and Human Services.

This research has been conducted using the UK Biobank resource, application 7089. Funding support for participating studies in the meta-analysis can be found in the Supplementary Note.

Author information

Author notes

    • Dajiang J Liu
    • , Gina M Peloso
    • , Haojie Yu
    • , Adam S Butterworth
    • , Xiao Wang
    • , Anubha Mahajan
    • , Danish Saleheen
    • , Connor Emdin
    • , Cristen J Willer
    •  & Sekar Kathiresan

    These authors contributed equally to this work.

    • Joanna M M Howson
    • , John Danesh
    • , Mark I McCarthy
    • , Chad A Cowan
    • , Goncalo Abecasis
    • , Panos Deloukas
    • , Kiran Musunuru
    • , Cristen J Willer
    •  & Sekar Kathiresan

    These authors jointly directed this work

Affiliations

  1. Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA

    • Dajiang J Liu
  2. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Gina M Peloso
    • , L Adrienne Cupples
    •  & Yanhua Zhou
  3. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Gina M Peloso
    • , Connor Emdin
    • , Tõnu Esko
    • , Joel N Hirschhorn
    • , Amit V Khera
    • , Derek Klarin
    • , Alisa K Manning
    • , James B Meigs
    • , Aniruddh P Patel
    •  & Sekar Kathiresan
  4. Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

    • Haojie Yu
    •  & Chad A Cowan
  5. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Adam S Butterworth
    • , Danish Saleheen
    • , Emanuele Di Angelantonio
    • , Rajiv Chowdhury
    • , Praveen Surendran
    • , Robin Young
    • , Joanna M M Howson
    •  & John Danesh
  6. The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK.

    • Adam S Butterworth
    • , Emanuele Di Angelantonio
    •  & John Danesh
  7. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Xiao Wang
    •  & Kiran Musunuru
  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Anubha Mahajan
    • , Andrew P Morris
    • , Neil R Robertson
    • , Lorraine Southam
    • , Natalie R van Zuydam
    •  & Mark I McCarthy
  9. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Danish Saleheen
  10. Center for Non-Communicable Diseases, Karachi, Pakistan.

    • Danish Saleheen
    • , Philippe Frossard
    • , Sehrish Jabeen
    •  & Asif Rasheed
  11. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Connor Emdin
    • , Amit V Khera
    • , Derek Klarin
    • , Alisa K Manning
    • , Aniruddh P Patel
    •  & Sekar Kathiresan
  12. ICDDR, B, Dhaka, Bangladesh.

    • Dewan Alam
  13. Imperial College London, London, UK.

    • Alexessander Couto Alves
    •  & Marjo-Riitta Jarvelin
  14. Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167–RID–AGE–Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France.

    • Philippe Amouyel
  15. Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France.

    • Dominique Arveiler
  16. VA Palo Alto Health Care System, Palo Alto, California, USA.

    • Themistocles L Assimes
    •  & Philip S Tsao
  17. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Themistocles L Assimes
    •  & Philip S Tsao
  18. Zilber School of Public Health, University of Wisconsin–Milwaukee, Milwaukee, Wisconsin, USA.

    • Paul L Auer
  19. Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Usman Baber
    • , Valentin Fuster
    •  & Roxana Mehran
  20. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

    • Christie M Ballantyne
  21. Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Lia E Bang
  22. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.

    • Marianne Benn
    • , Ruth Frikke-Schmidt
    •  & Anne Tybjaerg-Hansen
  23. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Marianne Benn
    • , Ruth Frikke-Schmidt
    •  & Anne Tybjaerg-Hansen
  24. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
    •  & Bruce M Psaty
  25. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Michael Boehnke
    • , Lars G Fritsche
    • , Anne U Jackson
    • , Xueling Sim
    • , Heather M Stringham
    • , Joshua Weinstock
    •  & Goncalo Abecasis
  26. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
    • , Megan L Grove
    •  & Alanna C Morrison
  27. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Eric Boerwinkle
  28. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Jette Bork-Jensen
    • , Niels Grarup
    • , Torben Hansen
    • , Johanne M Justesen
    •  & Oluf Pedersen
  29. The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.

    • Erwin P Bottinger
    • , Ruth J F Loos
    •  & Yingchang Lu
  30. Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.

    • Ivan Brandslund
  31. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.

    • Ivan Brandslund
  32. Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Morris Brown
    • , Mark J Caulfield
    • , Patricia B Munroe
    •  & Helen R Warren
  33. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.

    • Fabio Busonero
    • , Francesco Cucca
    • , Andrea Maschio
    • , Antonella Mulas
    • , Giorgio Pistis
    • , Serena Sanna
    •  & Magdalena Zoledziewska
  34. The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK.

    • Mark J Caulfield
  35. NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.

    • Mark J Caulfield
    • , Patricia B Munroe
    •  & Helen R Warren
  36. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • John C Chambers
    •  & Weihua Zhang
  37. Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK.

    • John C Chambers
    •  & Jaspal S Kooner
  38. Imperial College Healthcare NHS Trust, London, UK.

    • John C Chambers
    •  & Jaspal S Kooner
  39. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Daniel I Chasman
    • , Audrey Y Chu
    • , Franco Giulianini
    •  & Paul M Ridker
  40. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman
  41. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Y Eugene Chen
    • , Santhi K Ganesh
    • , Xiangfeng Lu
    • , Jonas B Nielsen
    • , He Zhang
    •  & Cristen J Willer
  42. The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor–UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA.

    • Yii-Der Ida Chen
    • , Jerome I Rotter
    •  & Kent D Taylor
  43. Medical Department, Lillebaelt Hospital, Vejle, Denmark.

    • Cramer Christensen
  44. NHLBI Framingham Heart Study, Framingham, Massachusetts, USA.

    • Audrey Y Chu
    •  & L Adrienne Cupples
  45. Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

    • John M Connell
    • , Colin N A Palmer
    •  & Natalie R van Zuydam
  46. Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.

    • Francesco Cucca
  47. Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA.

    • Scott M Damrauer
  48. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Scott M Damrauer
  49. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Gail Davies
    • , Ian J Deary
    • , David C M Liewald
    •  & John M Starr
  50. Department of Psychology, University of Edinburgh, Edinburgh, UK.

    • Gail Davies
    • , Ian J Deary
    •  & David C M Liewald
  51. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.

    • George Dedoussis
    •  & Aliki-Eleni Farmaki
  52. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Joshua C Denny
    •  & Dan M Roden
  53. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Joshua C Denny
    • , Dan M Roden
    • , Christian M Shaffer
    •  & Peter E Weeke
  54. British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

    • Anna Dominiczak
    • , Sandosh Padmanabhan
    •  & Naveed Sattar
  55. Montreal Heart Institute, Montreal, Quebec, Canada.

    • Marie-Pierre Dubé
    • , John D Rioux
    •  & Jean-Claude Tardif
  56. Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada.

    • Marie-Pierre Dubé
  57. Université de Montréal, Montreal, Quebec, Canada.

    • Marie-Pierre Dubé
    •  & Jean-Claude Tardif
  58. Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland.

    • Tapani Ebeling
  59. The Icelandic Heart Association, Kopavogur, Iceland.

    • Gudny Eiriksdottir
    • , Vilmundur Gudnason
    • , Johanna Jakobsdottir
    •  & Albert V Smith
  60. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Reedik Mägi
    •  & Andres Metspalu
  61. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Mary F Feitosa
  62. Research Centre in Epidemiology and Preventive Medicine–EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy.

    • Marco Ferrario
  63. Department of Epidemiology, UMR 1027–INSERM, Toulouse University–CHU Toulouse, Toulouse, France.

    • Jean Ferrieres
  64. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.

    • Ian Ford
  65. Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Myriam Fornage
    •  & Li An Lin
  66. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.

    • Paul W Franks
    • , Frida Renström
    •  & Tibor V Varga
  67. Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.

    • Paul W Franks
  68. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Paul W Franks
  69. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

    • Timothy M Frayling
    • , Dorota Pasko
    •  & Hanieh Yaghootkar
  70. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

    • Valentin Fuster
  71. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Santhi K Ganesh
    •  & Cristen J Willer
  72. Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China.

    • Wei Gao
  73. National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Melissa E Garcia
  74. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

    • Christian Gieger
    • , Harald Grallert
    •  & Annette Peters
  75. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
    • , Harald Grallert
    •  & Melanie Waldenberger
  76. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
    • , Harald Grallert
    • , Martina Müller-Nurasyid
    • , Annette Peters
    •  & Melanie Waldenberger
  77. Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Mark O Goodarzi
  78. Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Mark O Goodarzi
  79. Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden.

    • Leif Groop
  80. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Vilmundur Gudnason
    •  & Albert V Smith
  81. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

    • Torben Hansen
  82. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  83. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Caroline Hayward
    •  & Jennifer Huffman
  84. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  85. Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway.

    • Oddgeir L Holmen
  86. St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

    • Oddgeir L Holmen
  87. Department of Cardiology, Peking University First Hospital, Beijing, China.

    • Yong Huo
    •  & Yan Zhang
  88. K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

    • Kristian Hveem
  89. Department of Health Sciences, University of Iceland, Reykjavik, Iceland.

    • Johanna Jakobsdottir
  90. The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark.

    • Gorm B Jensen
  91. Steno Diabetes Center, Gentofte, Denmark.

    • Marit E Jørgensen
  92. National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark.

    • Marit E Jørgensen
  93. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.

    • J Wouter Jukema
    •  & Stella Trompet
  94. The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.

    • J Wouter Jukema
  95. Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

    • Pia R Kamstrup
    • , Anne Langsted
    • , Sune F Nielsen
    • , Børge G Nordestgaard
    •  & Anette Varbo
  96. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Stavroula Kanoni
    • , Eirini Marouli
    • , Kathleen E Stirrups
    •  & Panos Deloukas
  97. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Fredrik Karpe
    • , Matt J Neville
    • , Neil R Robertson
    • , Naveed Sattar
    •  & Mark I McCarthy
  98. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.

    • Fredrik Karpe
    •  & Mark I McCarthy
  99. UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK.

    • Frank Kee
  100. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA.

    • Derek Klarin
    •  & Christoper J O'Donnell
  101. Department of Health, National Institute for Health and Welfare, Helsinki, Finland.

    • Heikki A Koistinen
    • , Kari Kuulasmaa
    • , Markus Perola
    • , Veikko Salomaa
    •  & Jarmo Virtamo
  102. Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

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

    • Heikki A Koistinen
  104. National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

    • Jaspal S Kooner
  105. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Charles Kooperberg
    •  & Alex P Reiner
  106. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  107. Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.

    • Timo Lakka
  108. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

    • Timo Lakka
    •  & Rainer Rauramaa
  109. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.

    • Timo Lakka
    •  & Rainer Rauramaa
  110. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.

    • Claudia Langenberg
    • , Robert A Scott
    •  & Nick J Wareham
  111. Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark.

    • Anne Langsted
    • , Sune F Nielsen
    • , Børge G Nordestgaard
    •  & Anette Varbo
  112. Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark.

    • Torsten Lauritzen
  113. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.

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

    • Allan Linneberg
  115. Research Center for Prevention and Health, Copenhagen, Denmark.

    • Allan Linneberg
    •  & Charlotta Pisinger
  116. The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  117. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Xiangfeng Lu
  118. Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

    • Anders Malarstig
  119. Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden.

    • Anders Malarstig
  120. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul
    •  & Stephen S Rich
  121. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Alisa K Manning
    •  & James B Meigs
  122. Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Pekka Mäntyselkä
  123. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

    • Nicholas G D Masca
    •  & Nilesh J Samani
  124. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

    • Nicholas G D Masca
    •  & Nilesh J Samani
  125. Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • James B Meigs
  126. Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.

    • Olle Melander
    •  & Marju Orho-Melander
  127. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  128. Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany.

    • Martina Müller-Nurasyid
  129. DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany.

    • Martina Müller-Nurasyid
    • , Annette Peters
    •  & Melanie Waldenberger
  130. Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain.

    • Jose M Ordovas
  131. IMDEA-Alimentacion, Madrid, Spain.

    • Jose M Ordovas
  132. Nutrition and Genomics Laboratory, Jean Mayer–USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.

    • Jose M Ordovas
  133. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Christoper J O'Donnell
    • , Aniruddh P Patel
    •  & Sekar Kathiresan
  134. Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.

    • Cliona M Molony
    •  & Dermot F Reilly
  135. G3 Pharmaceuticals, Lexington, Massachusetts, USA.

    • Pieter Muntendam
  136. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aniruddh P Patel
    •  & Sekar Kathiresan
  137. Institute of Molecular Medicine FIMM, University of Helsinki, Finland.

    • Markus Perola
  138. Faculty of Medicine, University of Split, Split, Croatia.

    • Ozren Polasek
  139. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • Ozren Polasek
    •  & Igor Rudan
  140. International Centre for Circulatory Health, Imperial College London, London, UK.

    • Neil Poulter
    •  & Peter Sever
  141. Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.

    • Bruce M Psaty
  142. Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  143. Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
  144. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Alex P Reiner
  145. Department of Biobank Research, Umeå University, Umeå, Sweden.

    • Frida Renström
  146. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

    • Ellen M Schmidt
    • , Elizabeth K Speliotes
    • , Wei Zhou
    •  & Cristen J Willer
  147. Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.

    • Raquel S Sevilla
  148. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Xueling Sim
  149. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    • Suthesh Sivapalaratnam
  150. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Kerrin S Small
    •  & Timothy D Spector
  151. Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

    • Blair H Smith
  152. Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.

    • Blair H Smith
  153. Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.

    • Sangeetha Somayajula
  154. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.

    • Lorraine Southam
    • , Eleftheria Zeggini
    •  & John Danesh
  155. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.

    • Elizabeth K Speliotes
  156. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.

    • John M Starr
  157. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Kathleen E Stirrups
  158. Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Nathan Stitziel
  159. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Nathan Stitziel
  160. IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany.

    • Konstantin Strauch
  161. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Konstantin Strauch
  162. Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

    • Hayato Tada
  163. Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA.

    • Alan R Tall
    •  & Nan Wang
  164. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

    • Hua Tang
  165. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

    • Stella Trompet
  166. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Tuomilehto
  167. Dasman Diabetes Institute, Dasman, Kuwait.

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

    • Jaakko Tuomilehto
  169. Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia.

    • Jaakko Tuomilehto
  170. The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

    • Peter E Weeke
  171. Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA.

    • Jennifer Wessel
  172. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Jennifer Wessel
  173. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • James G Wilson
  174. Atlanta VA Medical Center, Decatur, Georgia, USA.

    • Peter W F Wilson
  175. Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA.

    • Peter W F Wilson
  176. Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.

    • Ming Xu
  177. Yale College, Yale University, New Haven, Connecticut, USA.

    • Neil S Zheng
  178. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Chad A Cowan
  179. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

    • Panos Deloukas

Consortia

  1. Charge Diabetes Working Group

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

  2. The EPIC-InterAct Consortium

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

  3. EPIC-CVD Consortium

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

  4. GOLD Consortium

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

  5. VA Million Veteran Program

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

Authors

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Contributions

All authors contributed to and approved the results and comments on the manuscript. Writing: C.J.W., D.J.L., G.M.P., G.A., P.D., X.L., and S. Kathiresan. Study supervision: S. Kathiresan. Primary analysis: D.J.L. and G.M.P. Secondary analysis: A.V.K., A. Mahajan, Charge Diabetes Working Group, C.M.M., C.E., D.J.R., D.F.R., D.P., E.K.S., E.M.S., GOLD Consortium, J.B.M., J. Wessel, L.G.F., M.O.G., M.I.M., M. Boehnke, N. Stitziel, R.S.S., S. Somayajula, VA Million Veteran Program, and X.L. Functional characterization: A.R.T., C.A.C., H. Yu, K.M., N.W., and X.W. Contribution to study-specific analysis: A.S.B., A.C.A., A.C.M., A.D., A.-E.F., A.K.M., A. Langsted, A. Linneberg, A. Malarstig, A. Manichaikul, A. Maschio, A. Metspalu, A. Mulas, A.P., A.P.M., A.P.P., A.P.R., A.R., A.T.-H., A.U.J., A.V., A.V.S., A.Y.C., B.G.N., B.H.S., B.M.P., C.C., C.G., C.H., C.J.O'D., C.J.W., C.L., C.K., C.M.B., C.M.S., C.N.A.P., C.P., D. Alam, D. Arveiler, D.C.M.L., D.I.C., D.J.L., D.K., D.M.R., D.S., E.B., E.d.A., E.M., E.P.B., EPIC-CVD Consortium, The EPIC-InterAct Consortium, E.Z., F.B., F.C., F.G., F. Karpe, F. Kee, F.R., G.B.J., G. Davies, G. Dedoussis, G.E., G.M.P., G.P., H.A.K., H.G., H.M.S., H.R.W., H. Tada, H. Tang, H. Yaghootkar, H.Z., I.B., I.F., I.J.D., I.R., J.C.B., J.B.-J., J.C.C., J.C.D., J.D., J.D.R., J.F., J.G.W., J.H., J.I.R., J.J., J.K., J.M.C., J.M.M.H., J.M.J., J.M.O., J.M.S., J.B.N., J.N.H., J.S.K., J.-C.T., J.T., J.V., J. Weinstock, J.W.J., K.D.T., K.E.S., K.H., K.K., K.S., K.S.S., L.A.C., L.A.L., L.E.B., L.G., L.J.L., L.S., M. Benn, M. Brown, M.J.C., M.-P.D., M.E.G., M.E.J., M. Ferrario, M.F.F., M. Fornage, M.-R.J., M.J.N., M.L., M.L.G., M.M.-N., M.O.-M., M.P., M.W., M.X., M.Z., N.G., N.G.D.M., N.J.S., N.J.W., N.P., N.R.R., N.R.v.Z., N. Sattar, N.S.Z., O.L.H., O.M., O. Pedersen, O. Polasek, P.A., P.B.M., P.D., P.E.W., P.F., P.L.A., P. Mäntyselkä, P.M.R., P. Muntendam, P.R.K., P. Sever, P.S.T., P. Surendran, P.W.F., P.W.F.W., R.A.S., R.C., R.F.-S., R.J.F.L., R. Magi, R. Mehran, R.R., R.Y., S.P., S.F.N., S.J., S. Kanoni, S. Kathiresan, S.K.G., S.M.D., S. Sanna, S. Sivapalaratnam, S.S.R., S.T., T.B.H., T.D.S., T. Ebeling, T.E.-I.C., T. Esko, T.H., T.L.A., T. Lakka, T. Lauritzen, T.M.F., T.V.V., U.B., V.F., V.G., V.S., W.G., W. Zhang, W. Zhou, X.S., Y.E.C., Y.H., Y.-D.I.C., Y.L., Y. Zhang, and Y. Zhou.

Competing interests

S. Kathiresan has received grant support from Bayer Healthcare and Amarin; holds equity in San Therapeutics and Catabasis; and has received personal fees for participation in scientific advisory boards for Bayer Healthcare, Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly Company, Leerink Partners, Noble Insights, and Ionis Pharmaceuticals. All other authors have no relationships relevant to the contents of this paper to disclose. Merck authors are employees of Merck Sharp Dohme Corp., New Jersey, USA.

Corresponding authors

Correspondence to Cristen J Willer or Sekar Kathiresan.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14 and Supplementary Note

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Studies contributing to meta-analysis

  2. 2.

    Supplementary Table 2

    Descriptive statistics for lipid levels across contributing studies.

  3. 3.

    Supplementary Table 3

    Genotyping and analysis methods across contributing studies

  4. 4.

    Supplementary Table 4

    Variant site distribution by alternative allele frequency and annotations

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    Supplementary Table 5

    Forty new loci where non-protein-altering variants are associated with lipid levels

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    Supplementary Table 6

    Reason for non-coding variants on array

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    Supplementary Table 7

    Association results in current study for 175 previously reported GWAS variants

  8. 8.

    Supplementary Table 8

    Association analysis of novel lipid loci in samples of European American, African American, South Asian, and Hispanic ancestries.

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    Supplementary Table 9

    Gene-level association results

  10. 10.

    Supplementary Table 10

    Replication results for 75 novel primary associations

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    Supplementary Table 11

    Variance explained by known and independently associated SNPs

  12. 12.

    Supplementary Table 12

    Association Results for 444 independently associated variants with lipid traits

  13. 13.

    Supplementary Table 13

    Loci where protein-altering variant is top signal or protein-altering variant explains the GWAS signal

  14. 14.

    Supplementary Table 14

    59 loci where there's a protein-altering variant that is either the top signal, explains the signal or is independent.

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    Supplementary Table 15

    Association results for null mutations with p < 0.001

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    Supplementary Table 16

    HDL-C variants and risk for age-related macular degeneration (AMD)

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    Supplementary Table 17

    DNA variants in CETP robustly associate with HDL-C and risk for AMD

  18. 18.

    Supplementary Table 18

    Thirty studies from populations of European ancestry contributing to PCSK9 p.R46L on risk of T2D

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    Supplementary Table 19

    Association of LDL-C variants with coronary artery disease (CAD) and type 2 diabetes (T2D)

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    Supplementary Table 20

    Definitions of outcomes in UK Biobank PheWAS

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    Supplementary Table 21

    sgRNA sequences for functional follow-up experiments

About this article

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DOI

https://doi.org/10.1038/ng.3977

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