Abstract
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10−8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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The power of genetic diversity in genome-wide association studies of lipids
Genetic architecture of human plasma lipidome and its link to cardiovascular disease
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Acknowledgements
We wish to dedicate this paper to the memory of Dr Leena Peltonen, who passed away on 11 March 2010. A full listing of acknowledgements is provided in Supplementary Information.
Author information
Tanya M. Teslovich, Kiran Musunuru, L. Adrienne Cupples, Manjinder S. Sandhu, Paul M Ridker, Daniel J. Rader, Cornelia M. van Duijn, Gonçalo R. Abecasis, Michael Boehnke and Sekar Kathiresan: These authors contributed equally to this work.
Leena Peltonen: Deceased.
Authors and Affiliations
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, Michigan, USA
Tanya M. Teslovich, Cristen J. Willer, Heather M. Stringham, Gonçalo R. Abecasis & Michael Boehnke
Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
Kiran Musunuru, James P. Pirruccello, Benjamin F. Voight, David Altshuler & Sekar Kathiresan
Cardiovascular Research Center, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
Kiran Musunuru & Sekar Kathiresan
Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA
Kiran Musunuru, Daniel I. Chasman, Robert Y. L. Zee, Christopher J. O’Donnell, David Altshuler, Paul M Ridker & Sekar Kathiresan
Broad Institute, Cambridge, 02142, Massachusetts, USA
Kiran Musunuru, James P. Pirruccello, Benjamin F. Voight, Candace Guiducci, Elena Gonzalez, Kenechi G. Ejebe, Gabriel Crawford, Noel P. Burtt, David Altshuler, Stacey B. Gabriel & Sekar Kathiresan
Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA
Kiran Musunuru & James P. Pirruccello
Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Kopavogur, 201, Iceland
Albert V. Smith & Vilmundur Gudnason
University of Iceland, Reykjavik, 101, Iceland
Albert V. Smith, Unnur Thorsteinsdottir, Vilmundur Gudnason & Kari Stefansson
Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA
Andrew C. Edmondson, Mingyao Li, Muredach P. Reilly & Daniel J. Rader
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA
Andrew C. Edmondson, Ioannis M. Stylianou, Mingyao Li, Muredach P. Reilly & Daniel J. Rader
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, 10032, New York, USA
Masahiro Koseki, David Masson & Alan R. Tall
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, FI-00014, Finland
Samuli Ripatti, Ida Surakka, Kaisa Silander, Juha Saharinen, Markus Perola & Jaakko Kaprio
National Institute for Health and Welfare, P.O. Box 104, FI-00251 Helsinki, Finland.,
Samuli Ripatti, Ida Surakka, Kaisa Silander, Markus Perola & Jaakko Kaprio
Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, 02215, Massachusetts, USA
Daniel I. Chasman, Robert Y. L. Zee, Lynda M. Rose & Paul M Ridker
Robarts Research Institute, University of Western Ontario, London, N6A 5K8, Ontario, Canada
Christopher T. Johansen & Robert A. Hegele
Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands
Sigrid W. Fouchier, G. Kees Hovingh & John J.P. Kastelein
Department of Epidemiology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.,
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Department of Biostatistics, Boston University School of Public Health, Boston, 02118, Massachusetts, USA
Gina M. Peloso, Serkalem Demissie & L. Adrienne Cupples
National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, 01702, Massachusetts, USA
Gina M. Peloso, Christopher J. O’Donnell, Serkalem Demissie & L. Adrienne Cupples
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, 77030, Texas, USA
Maja Barbalic & Eric Boerwinkle
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK
Sally L. Ricketts, Robert Luben, Kay-Tee Khaw & Manjinder S. Sandhu
Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, 98101, Washington, USA
Joshua C. Bis
deCODE Genetics, Reykjavik, 101, Iceland
Gudmar Thorleifsson, Hilma Holm, Unnur Thorsteinsdottir & Kari Stefansson
Division of Statistical Genomics in the Center for Genome Sciences, Washington University School of Medicine, St Louis, 63108, Missouri, USA
Mary F. Feitosa & Ingrid B. Borecki
Department of Epidemiology and Public Health, Imperial College London, London, W2 1PG, UK
John Chambers & Weihua Zhang
Department of Clinical Sciences, Lund University, Malmö, SE-20502, Sweden
Marju Orho-Melander, Olle Melander & Leif C. Groop
Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK
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Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA
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Center for Genome Science, National Institute of Health, Seoul, 122-701, Republic of Korea
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Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul, 151-742, Republic of Korea
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Department of Statistics, College of Natural Sciences, Seoul National University, Seoul, 151-742, Republic of Korea
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Department of Statistics, Sookmyung Women’s University, Seoul, 140-742, Republic of Korea
Kyunga Kim
Centre for Molecular Epidemiology, National University of Singapore, Singapore, 117597, Republic of Singapore
Xueling Sim
Genome Institute of Singapore, Singapore, 138672, Republic of Singapore
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Department of Genetics, University of North Carolina, Chapel Hill, 27599, North Carolina, USA
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Department of Genome Sciences, University of Washington, Seattle, 98195, Washington, USA
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Genetics Division, GlaxoSmithKline R&D, King of Prussia, 19406, Pennsylvania, USA
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MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
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Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria.,
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MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU, UK
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Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA) and Center of Medical Systems Biology (CMSB), Leiden, 2300 RC, The Netherlands
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Centre for Population Health Sciences, University of Edinburgh, Edinburgh, EH8 9AG, UK
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Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands.,
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Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, FI-00271, Finland
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Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, 21225, Maryland, USA
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Medstar Research Institute, Baltimore, 21218, Maryland, USA
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Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.,
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Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), Helsinki, FI-00029, Finland
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Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK
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Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.,
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Department of Clinical Chemistry, University of Oulu, FI-90220, Oulu, Finland
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The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa, Ottawa, K1Y 4W7, Canada
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Departments of Medicine, Epidemiology, and Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Seattle, 98101, Washington, USA
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Institut fur Humangenetik, Helmholtz Zentrum Munchen, Deutsches Forschungszentrum fur Umwelt und Gesundheit, Neuherberg, 85764, Germany
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Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Muenchen, 81675, Germany
Thomas Meitinger
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,
Mark I. McCarthy
Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK
Mark I. McCarthy
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, OX3 7LJ, UK
Mark I. McCarthy
Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol, BS8 2BN, UK
Wendy McArdle
Institute of Applied Genomics, via Linussio 51, 33100 Udine, Italy.,
Fabio Marroni
Cardiovascular Epidemiology and Genetics, Institut Municipal d’Investigacio Medica, Barcelona, 08003, Spain
Gavin Lucas
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, FI-00014, Finland
Marja-Liisa Lokki
Montreal Heart Institute (Research Center), Université de Montréal, Montréal, H1T 1C8, Québec, Canada
Guillaume Lettre
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, 20892, Maryland, USA
Lenore J. Launer & Tamara B. Harris
Science Center, Tampere University Hospital, Tampere, FI-33521, Finland
Reijo Laaksonen
Institute of Regional Health Research and the Danish Twin Registry, Institute of Public Health, University of Southern Denmark, JBWinsløws Vej 9B, DK-5000, Odense, Denmark.,
Kirsten O. Kyvik
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, FI-00014, Finland
Jaakko Kaprio
Massachusetts General Hospital Weight Center, Boston, 02114, Massachusetts, USA
Lee M. Kaplan
Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, SE-75185, Sweden
Åsa Johansson, Wilmar Igl & Ulf Gyllensten
Department of Epidemiology & Biostatistics, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK.,
Marjo-Riitta Jarvelin & Paul Elliott
Department of Public Health Science and General Practice, University of Oulu, Oulu, FI-90220, Finland
Marjo-Riitta Jarvelin
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, 93053, Germany
Christian Hengstenberg
Department of Epidemiology and Preventive Medicine Regensburg University Medical Center Franz-Josef-Strauss-Allee 11, Regensburg, 93053, Germany
Iris M. Heid
Department of Biomedical Engineering and Computational Science, Aalto University School of Science and Technology, Aalto, FI-00076, Finland
Aki S. Havulinna
LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK
Alistair S. Hall
Department of Medicine, Helsinki University Hospital, Helsinki, FI-00029, Finland
Leif C. Groop
Department of Psychiatry, Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 90095, California, USA
Nelson B. Freimer
Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, 21225, Maryland, USA
Luigi Ferrucci
Medizinische Klinik II, Universität zu Lübeck, Lübeck, 23538, Germany
Jeanette Erdmann & Heribert Schunkert
MRC-HPA Centre for Environment and Health, Imperial College London, London, W2 1PG, UK
Paul Elliott
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.,
Anna F. Dominiczak
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-17177, Sweden
Ulf de Faire
National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA
Francis S. Collins & Lori L. Bonnycastle
Departments of Vascular Medicine & Cardiology, Academic Medical Centre, Amsterdam, 1105 AZ, The Netherlands
S. Matthijs Boekholdt
Department of Physiology and Biophysics, University of Southern California, Los Angeles, 90033, California, USA
Richard N. Bergman
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, 50125, Italy
Stefania Bandinelli
Department of Medicine, Baylor College of Medicine, Houston, 77030, Texas, USA
Christie M. Ballantyne
Department of Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA
Themistocles L. Assimes & Thomas Quertermous
Singapore Eye Research Institute, National University of Singapore, Singapore, 168751, Republic of Singapore
Tien Y. Wong
Departments of Medicine/Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore
E-Shyong Tai
Office of Population Studies Foundation, University of San Carlos, Cebu City, 6000, Philippines
Alan B. Feranil
Department of Anthropology, Northwestern University, Evanston, 60208, Illinois, USA
Christopher W. Kuzawa
Department of Nutrition, Carolina Population Center, University of North Carolina, Chapel Hill, 27516, North Carolina, USA
Linda S. Adair
Department of Medicine, University of Mississippi Medical Center, Jackson, 39126, Mississippi, USA
Herman A. Taylor Jr & James G. Wilson
Children’s Hospital Oakland Research Institute, Oakland, 94609, California, USA
Ronald M. Krauss
Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares, Madrid, 28029, Spain
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Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Nutrition and Genomics Laboratory, Boston, 02111, Massachusetts, USA
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Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.,
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Sage Bionetworks, Seattle, 98109, Washington, USA
Eric E. Schadt
Division of Community Health Sciences, St George’s University of London, London, SW17 0RE, UK
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Department of Cardiovascular Sciences, University of Leicester, NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, LE3 9QP, UK
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Contributions
T.M.T., K.M., A.V.S., A.C.E., I.M.S., M.K. and J.P.P. carried out the primary data analyses and/or experimental work. All other authors contributed to additional analyses. L.A.C., M.S.S., P.M.R., D.J.R., C.M.v.D., L.P., G.R.A., M.B. and S.K. conceived, designed, and supervised the study. K.M. wrote the manuscript.
Corresponding author
Correspondence to Sekar Kathiresan.
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Competing interests
Competing interests: D.M.W., K.S. and V.M. are full-time employees of GlaxoSmithKline. M.S.S. has received research funding from GlaxoSmithKline. P.V. and G.W. received grant money from GlaxoSmithKline to fund the CoLaus study. G.T., K.S., U.T. and H.H. are full-time employees of deCODE genetics. The other authors declare no competing financial interests.
Supplementary information
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This file contains Supplementary Methods, References, Supplementary Figures 1-3 with legends, Supplementary Tables 1-19 and a full list of Acknowledgments. (PDF 2944 kb)
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Teslovich, T., Musunuru, K., Smith, A. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010). https://doi.org/10.1038/nature09270
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DOI: https://doi.org/10.1038/nature09270
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