Article | Published:

Discovery and refinement of loci associated with lipid levels

Nature Genetics volume 45, pages 12741283 (2013) | Download Citation

Abstract

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

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Acknowledgements

We especially thank the more than 196,000 volunteers who participated in our study. Detailed acknowledgment of funding sources is provided in the Supplementary Note.

Author information

Author notes

    • Cristen J Willer
    • , Ellen M Schmidt
    •  & Sebanti Sengupta

    These authors contributed equally to this work.

    • Cristen J Willer
    • , Michael Boehnke
    • , Panos Deloukas
    • , Sekar Kathiresan
    • , Karen L Mohlke
    • , Erik Ingelsson
    •  & Gonçalo R Abecasis

    These authors jointly directed this work.

Affiliations

  1. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.

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

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

    • Cristen J Willer
  4. 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
    •  & Gonçalo R Abecasis
  5. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Gina M Peloso
    •  & L Adrienne Cupples
  6. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Gina M Peloso
    • , Ron Do
    • , Richa Saxena
    •  & Sekar Kathiresan
  7. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Gina M Peloso
    • , Tõnu Esko
    • , Pierre Fontanillas
    • , Cameron D Palmer
    • , Sailaja Vedantam
    • , Joel N Hirschhorn
    •  & Sekar Kathiresan
  8. Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.

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

    • Stefan Gustafsson
    • , Andrea Ganna
    • , Ci Song
    •  & Erik Ingelsson
  10. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, 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
  11. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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

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

    • Samia Mora
    • , Paul M Ridker
    •  & Daniel I Chasman
  14. Harvard Medical School, Boston, Massachusetts, USA.

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

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

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

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

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

    • Heleen M Den Hertog
    • , Evita G Van den Herik
    •  & Peter J Koudstaal
  20. 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
  21. Cardiology, Department of Specialities of Medicine, Geneva University Hospital, Geneva, Switzerland.

    • Georg B Ehret
    •  & François Mach
  22. 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
  23. Estonian Genome Center of the University of Tartu, Tartu, Estonia.

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

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

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

    • Teresa Ferreira
    • , Cecilia M Lindgren
    • , Mark I McCarthy
    •  & Erik Ingelsson
  27. 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
  28. 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
  29. Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Kauko Heikkilä
    •  & Jaakko Kaprio
  30. 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
  31. Centre for Medical Systems Biology, Leiden, The Netherlands.

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

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

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

    • Toby Johnson
    •  & Patricia B Munroe
  35. 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
  36. Biocenter Oulu, University of Oulu, Oulu, Finland.

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

    • Marika Kaakinen
    • , Paul Elliott
    •  & Marjo-Riitta Järvelin
  38. 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
  39. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

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

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

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

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

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

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

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

    • Massimo Mangino
    •  & Tim D Spector
  47. 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
  48. Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

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

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

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

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

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

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

    • Serena Sanna
    •  & Carlo Sidore
  55. 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
  56. Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Weihua Zhang
    •  & John C Chambers
  71. Ealing Hospital, Southall, UK.

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

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

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

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

    • Latonya F Been
    • , Martha L Gravito
    •  & Dharambir K Sanghera
  76. 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
  77. Department of Experimental Medicine, University of Milano-Bicocca, Milan, Italy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Pirjo Komulainen
    • , Timo A Lakka
    •  & Rainer Rauramaa
  99. 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
  100. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaana Lindström
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  101. 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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  102. The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  103. The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  104. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle
  105. Institute for Medical Informatics and Biometrics, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.

    • Gabrielle Müller
  106. Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.

    • Ramaiah Nagaraja
  107. Department of Clinical Pharmacology, University of Tampere School of Medicine, Tampere, Finland.

    • Tuomo V M Nieminen
  108. Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland.

    • Tuomo V M Nieminen
  109. Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

    • Tuomo V M Nieminen
  110. Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland.

    • Isleifur Olafsson
  111. Department of Medical Genetics, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    • Aarno Palotie
  112. Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Aarno Palotie
  113. Department of Statistical Sciences, University College London, London, UK.

    • Theodore Papamarkou
  114. National Institute for Health and Welfare, Oulu, Finland.

    • Anneli Pouta
    •  & Marjo-Riitta Järvelin
  115. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Translational Research Center, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
    •  & Muredach P Reilly
  116. 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
  117. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

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

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

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

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

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

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

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

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

    • Alena Stancáková
  126. INSERM UMRS 937, Pierre and Marie Curie University, Paris, France.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Antero Kesäniemi
  165. National Heart & Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Danish Saleheen
  183. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Jose M Ordovas
  201. 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
  202. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

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

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

    • Stephen S Rich
  205. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  206. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Sekar Kathiresan

Consortia

  1. Global Lipids Genetics Consortium

Authors

    Contributions

    Writing and analysis group: G.R.A., M. Boehnke, L.A.C., P.D., P.W.F., S. Kathiresan, K.L.M., E.I., G.M.P., S.S.R., S.R., M.S.S., E.M.S., S. Sengupta and C.J.W. (Lead). E.M.S. and S. Sengupta performed meta-analysis, and E.M.S., S. Sengupta, G.M.P., M.L.B., J.C., S.G., A.G. and S. Kanoni performed bioinformatics analyses. E.M.S. and S. Sengupta prepared the tables, figures and supplementary material. C.J.W. led the analysis and bioinformatics efforts. E.I. and K.L.M. led the biological interpretation of results. C.J.W. and G.R.A. wrote the manuscript. All analysis and writing group authors extensively discussed the analysis, results, interpretation and presentation of results.

    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.J.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.J.W.; (FIN-D2D 27) 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.J., D.I.B., N.L.P. and T.D.S.; (GLACIER) P.W.F., 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.G.; (LifeLines) B.H.R.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) B.O.B. and W.M.; (MDC) L.C.G. and S. Kathiresan; (MEDSTAR) M.S.B., 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 27) 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.M., P.E. and S.V.; (NSPHS and FRISCII) Å.J.; (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) D.I.C., S.M. 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.J.; (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.J.; (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 27) A.U.J.; (FINCAVAS) L.-P.L.; (Framingham) L.A.C. and G.M.P.; (FRISCII and NSPHS) Å.J.; (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.J.; (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.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.

    Corresponding authors

    Correspondence to Cristen J Willer or Karen L Mohlke or Erik Ingelsson or Gonçalo R Abecasis.

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    https://doi.org/10.1038/ng.2797