Tanya M. Teslovich, Kiran Musunuru, Albert V. Smith, Andrew C. Edmondson, Ioannis M. Stylianou, Masahiro Koseki, James P. Pirruccello, Samuli Ripatti, Daniel I. Chasman, Cristen J. Willer, Christopher T. Johansen, Sigrid W. Fouchier, Aaron Isaacs, Gina M. Peloso, Maja Barbalic, Sally L. Ricketts, Joshua C. Bis, Yurii S. Aulchenko, Gudmar Thorleifsson, Mary F. Feitosa, John Chambers, Marju Orho-Melander, Olle Melander, Toby Johnson, Xiaohui Li, Xiuqing Guo, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C. Croteau-Chonka, Leslie A. Lange, Joshua D. Smith, Kijoung Song, Jing Hua Zhao, Xin Yuan, Jian'an Luan, Claudia Lamina, Andreas Ziegler, Weihua Zhang, Robert Y. L. Zee, Alan F. Wright, Jacqueline C. M. Witteman, James F. Wilson, Gonneke Willemsen, H.-Erich Wichmann, John B. Whitfield, Dawn M. Waterworth, Nicholas J. Wareham, Gãrard Waeber, Peter Vollenweider, Benjamin F. Voight, Veronique Vitart, Andre G. Uitterlinden, Manuela Uda, Jaakko Tuomilehto, John R. Thompson, Toshiko Tanaka, Ida Surakka, Heather M. Stringham, Tim D. Spector, Nicole Soranzo, Johannes H. Smit, Juha Sinisalo, Kaisa Silander, Eric J. G. Sijbrands, Angelo Scuteri, James Scott, David Schlessinger, Serena Sanna, Veikko Salomaa, Juha Saharinen, Chiara Sabatti, Aimo Ruokonen, Igor Rudan, Lynda M. Rose, Robert Roberts, Mark Rieder, Bruce M. Psaty, Peter P. Pramstaller, Irene Pichler, Markus Perola, Brenda W. J. H. Penninx, Nancy L. Pedersen, Cristian Pattaro, Alex N. Parker, Guillaume Pare, Ben A. Oostra, Christopher J. O'donnell, Markku S. Nieminen, Deborah A. Nickerson, Grant W. Montgomery, Thomas Meitinger, Ruth Mcpherson, Mark I. Mccarthy, Wendy Mcardle, David Masson, Nicholas G. Martin, Fabio Marroni, Massimo Mangino, Patrik K. E. Magnusson, Gavin Lucas, Robert Luben, Ruth J. F. Loos, Marja-Liisa Lokki, Guillaume Lettre, Claudia Langenberg, Lenore J. Launer, Edward G. Lakatta, Reijo Laaksonen, Kirsten O. Kyvik, Florian Kronenberg, Inke R. König, Kay-Tee Khaw, Jaakko Kaprio, Lee M. Kaplan, Å Johansson, Marjo-Riitta Jarvelin, A. Cecile J. W. Janssens, Erik Ingelsson, Wilmar Igl, G. Kees Hovingh, Jouke-Jan Hottenga, Albert Hofman, Andrew A. Hicks, Christian Hengstenberg, Iris M. Heid, Caroline Hayward, Aki S. Havulinna, Nicholas D. Hastie, Tamara B. Harris, Talin Haritunians, Alistair S. Hall, Ulf Gyllensten, Candace Guiducci, Leif C. Groop, Elena Gonzalez, Christian Gieger, Nelson B. Freimer, Luigi Ferrucci, Jeanette Erdmann, Paul Elliott, Kenechi G. Ejebe, Angela Döring, Anna F. Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Eco J. C. De Geus, Ulf De Faire, Gabriel Crawford, Francis S. Collins, Yii-Der I. Chen, Mark J. Caulfield, Harry Campbell, Noel P. Burtt, Lori L. Bonnycastle, Dorret I. Boomsma, S. Matthijs Boekholdt, Richard N. Bergman, Inês Barroso, Stefania Bandinelli, Christie M. Ballantyne, Themistocles L. Assimes, Thomas Quertermous, David Altshuler, Mark Seielstad, Tien Y. Wong, E-Shyong Tai, Alan B. Feranil, Christopher W. Kuzawa, Linda S. Adair, Herman A. Taylor Jr., Ingrid B. Borecki, Stacey B. Gabriel, James G. Wilson, Hilma Holm, Unnur Thorsteinsdottir, Vilmundur Gudnason, Ronald M. Krauss, Karen L. Mohlke, Jose M. Ordovas, Patricia B. Munroe, Jaspal S. Kooner, Alan R. Tall, Robert A. Hegele, John J.P. Kastelein, Eric E. Schadt, Jerome I. Rotter, Eric Boerwinkle, David P. Strachan, Vincent Mooser, Kari Stefansson, Muredach P. Reilly, Nilesh J Samani, Heribert Schunkert, L. Adrienne Cupples, Manjinder S. Sandhu, Paul M Ridker, Daniel J. Rader, Cornelia M. Van Duijn, Leena Peltonen, Gonãalo R. Abecasis, Michael Boehnke, Sekar Kathiresan
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<-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. © 2010 Macmillan Publishers Limited. All rights reserved.
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, United States; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, United States; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, United States; Department of Medicine, Harvard Medical School, Boston, MA 02115, United States; Broad Institute, Cambridge, MA 02142, United States; Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Icelandic Heart Association, Heart Preventive Clinic, Research Institute, 201 Kopavogur, Ireland; University of Iceland, 101 Reykjavik, Iceland; Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States; Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States; Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, United States; Institute for Molecular Medicine Finland FIMM, University of Helsinki, FI-00014 Helsinki, Finland; National Institute for Health and Welfare, P.O. Box 104, FI-00251 Helsinki, Finland; Division of Preventive Medicine, Brigham andWomen's Hospital, Boston, MA 02215, United States; Robarts Research Institute, University of Western Ontario, London, ON N6A 5K8, Canada; Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, Netherlands; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, United States; National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, United States; Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, United States; Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, United Kingdom; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, United States; DeCODE Genetics, 101 Reykjavik, Iceland; Division of Statistical Genomics, Center for Genome Sciences, Washington University School of Medicine, St Louis, MO 63108, United States; Department of Epidemiology and Public Health, Imperial College London, London W21PG, United Kingdom; Department of Clinical Sciences, Lund University, SE-20502, Malmö, Sweden; Clinical Pharmacology, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States; Center for Genome Science, National Institute of Health, Seoul 122-701, South Korea; Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul 151-742, South Korea; Department of Statistics, College of Natural Sciences, Seoul National University, Seoul 151-742, South Korea; Department of Statistics, Sookmyung Women's University, Seoul 140-742, South Korea; Centre for Molecular Epidemiology, National University of Singapore, Singapore 117597, Singapore; Genome Institute of Singapore, Singapore 138672, Singapore; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, United States; Department of Genome Sciences, University of Washington, Seattle, WA 98195, United States; Genetics Division, GlaxoSmithKline R and D, King of Prussia, PA 19406, United States; MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Division of Genetic Epidemiology, Department of Medical Genetics, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, 23562 Lübeck, Germany; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, United Kingdom; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Center of Medical Systems Biology (CMSB), 2300 RC Leiden, Netherlands; Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom; Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, Netherlands; Institute of Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Genetic Epidemiology Unit, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, QLD 4029, Australia; Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, Netherlands; Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, C/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy; Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland; Department of Health Sciences, University of Leicester, Leicester LE1 6TP, United Kingdom; Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21225, United States; Medstar Research Institute, Baltimore, MD 21218, United States; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; Department of Psychiatry, EMGO Institute, VU University Medical Center, 1007 MB Amsterdam, Netherlands; Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), FI-00029 Helsinki, Finland; Unita Operativa Geriatria, Istituto Nazionale Ricovero e Cura Anziani (INRCA), Istituto Ricovero e Cura a Carattere Scientifico (IRCCS), Via Cassia 1167, 00189 Rome, Italy; Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London W12 0NN, United Kingdom; Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, United States; Department of Health Research and Policy, Stanford University, Stanford, CA 94305, United States; Department of Clinical Chemistry, University of Oulu, FI-90220 Oulu, Finland; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa, Ottawa K1Y 4W7, Canada; Departments of Medicine, Epidemiology, and Health Services, University of Washington, Group Health Research Institute, Seattle, WA 98101, United States; Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso 1, 39100 Bolzano, Italy; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden; Amgen, Thousand Oaks, CA 91320, United States; Genetic and Molecular Epidemiology Laboratory, McMaster University, Hamilton, ON L8N3Z5, Canada; Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands; Institut fur Humangenetik, Helmholtz Zentrum Munchen, Deutsches Forschungszentrum fur Umwelt und Gesundheit, 85764 Neuherberg, Germany; Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675 Muenchen, Germany; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol BS8 2BN, United Kingdom; Institute of Applied Genomics, via Linussio 51, 33100 Udine, Italy; Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigacio Medica, 08003 Barcelona, Spain; Transplantation Laboratory, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland; Montreal Heart Institute, Research Center, Université de Montréal, Montréal, QC H1T 1C8, Canada; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, United States; Science Center, Tampere University Hospital, FI-33521 Tampere, Finland; Institute of Regional Health Research, Institute of Public Health, University of Southern Denmark, JBWinsløws Vej 9B, DK-5000, Odense, Denmark; Faculty of Medicine, Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland; Massachusetts General Hospital Weight Center, Boston, MA 02114, United States; Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, SE-75185 Uppsala, Sweden; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, St Mary's Campus, London W2 1PG, United Kingdom; Department of Public Health Science and General Practice, University of Oulu, FI-90220 Oulu, Finland; Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany; Department of Epidemiology, Preventive Medicine Regensburg University Medical, Center Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Department of Biomedical Engineering and Computational Science, Aalto University School of Science and Technology, FI-00076 Aalto, Finland; LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom; Department of Medicine, Helsinki University Hospital, FI-00029 Helsinki, Finland; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States; Clinical Research Branch, National Institute on Aging, National Institutes Health, Baltimore, MD 21225, United States; Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany; MRC-HPA Centre for Environment and Health, Imperial College London, LondonW21PG, United Kingdom; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom; Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States; Departments of Vascular Medicine and Cardiology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands; Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA 90033, United States; Geriatric Unit, Azienda Sanitaria Firenze (ASF), 50125 Florence, Italy; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, United States; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States; Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Singapore; Departments of Medicine/Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Office of Population Studies Foundation, University of San Carlos, Cebu City 6000, Philippines; Department of Anthropology, Northwestern University, Evanston, IL 60208, United States; Department of Nutrition, Carolina Population Center, University of North Carolina, Chapel Hill, NC 27516, United States; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39126, United States; Children's Hospital Oakland Research Institute, Oakland, CA 94609, United States; Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain; Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States; London Genome Centre, London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Sage Bionetworks, Seattle, WA 98109, United States; Division of Community Health Sciences, St George's University of London, London SW17 0RE, United Kingdom; Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom; Affiliated Institute, University of Lübeck, Germany
