Biological, clinical and population relevance of 95 loci for blood lipids View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-08

AUTHORS

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, Gérard 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, Åsa 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, Gonçalo R. Abecasis, Michael Boehnke, Sekar Kathiresan

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. More... »

PAGES

707-713

Journal

TITLE

Nature

ISSUE

7307

VOLUME

466

Author Affiliations

  • Department of Biostatistics, Center for Statistical Genetics, University of Michigan, 48109, Ann Arbor, Michigan, USA
  • Johns Hopkins University School of Medicine, 21287, Baltimore, Maryland, USA
  • University of Iceland, 101, Reykjavik, Iceland
  • Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 19104, Philadelphia, Pennsylvania, USA
  • Division of Molecular Medicine, Department of Medicine, Columbia University, 10032, New York, New York, USA
  • National Institute for Health and Welfare, P.O. Box 104, FI-00251 Helsinki, Finland.
  • Division of Preventive Medicine, Brigham and Women’s Hospital, 02215, Boston, Massachusetts, USA
  • Robarts Research Institute, University of Western Ontario, N6A 5K8, London, Ontario, Canada
  • Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
  • Department of Epidemiology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
  • National Heart, Lung and Blood Institute’s Framingham Heart Study, 01702, Framingham, Massachusetts, USA
  • Human Genetics Center, University of Texas Health Science Center at Houston, 77030, Houston, Texas, USA
  • Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, CB1 8RN, Cambridge, UK
  • Cardiovascular Health Research Unit and Department of Medicine, University of Washington, 98101, Seattle, Washington, USA
  • deCODE Genetics, 101, Reykjavik, Iceland
  • Division of Statistical Genomics in the Center for Genome Sciences, Washington University School of Medicine, 63108, St Louis, Missouri, USA
  • Department of Epidemiology and Public Health, Imperial College London, W2 1PG, London, UK
  • Department of Clinical Sciences, Lund University, SE-20502, Malmö, Sweden
  • 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, EC1M 6BQ, London, UK
  • Medical Genetics Institute, Cedars-Sinai Medical Center, 90048, Los Angeles, California, USA
  • Center for Genome Science, National Institute of Health, 122-701, Seoul, Republic of Korea
  • Department of Statistics, College of Natural Sciences, Seoul National University, 151-742, Seoul, Republic of Korea
  • Department of Statistics, Sookmyung Women’s University, 140-742, Seoul, Republic of Korea
  • Centre for Molecular Epidemiology, National University of Singapore, 117597, Singapore, Republic of Singapore
  • Genome Institute of Singapore, 138672, Singapore, Republic of Singapore
  • Department of Genetics, University of North Carolina, 27599, Chapel Hill, North Carolina, USA
  • Department of Genome Sciences, University of Washington, 98195, Seattle, Washington, USA
  • Genetics Division, GlaxoSmithKline R&D, 19406, King of Prussia, Pennsylvania, USA
  • MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK
  • Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, 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, EH4 2XU, Edinburgh, UK
  • Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA) and Center of Medical Systems Biology (CMSB), 2300 RC, Leiden, The Netherlands
  • Centre for Population Health Sciences, University of Edinburgh, EH8 9AG, Edinburgh, UK
  • Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The 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, 4029, Queensland, Australia
  • Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011, Lausanne, Switzerland
  • Broad Institute, 02142, Cambridge, Massachusetts, USA
  • Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The 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, LE1 6TP, Leicester, UK
  • Medstar Research Institute, 21218, Baltimore, Maryland, USA
  • Department of Twin Research and Genetic Epidemiology, King’s College London, SE1 7EH, London, UK
  • Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Department of Psychiatry, EMGO Institute, Neuroscience Campus Amsterdam, VU University Medical Center, 1007 MB, Amsterdam, The 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, W12 0NN, London, UK
  • Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
  • Institute for Molecular Medicine Finland FIMM, University of Helsinki, FI-00014, Helsinki, Finland
  • Department of Health Research and Policy, Stanford University, 94305, Stanford, California, USA
  • Department of Clinical Chemistry, University of Oulu, FI-90220, Oulu, Finland
  • The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa, K1Y 4W7, Ottawa, Canada
  • Departments of Medicine, Epidemiology, and Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, 98101, Seattle, Washington, USA
  • Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso 1, 39100 Bolzano, Italy – affiliated institute of the University of Lübeck, Germany
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177, Stockholm, Sweden
  • Amgen, Thousand Oaks, California 91320, USA.
  • Genetic and Molecular Epidemiology Laboratory, McMaster University, L8N3Z5, Hamilton, Ontario, Canada
  • Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands
  • Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675, Muenchen, Germany
  • Oxford NIHR Biomedical Research Centre, Churchill Hospital, OX3 7LJ, Oxford, UK
  • Avon Longitudinal Study of Parents and Children, University of Bristol, BS8 2BN, Bristol, UK
  • 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, H1T 1C8, Montréal, Québec, Canada
  • Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, 20892, Bethesda, Maryland, USA
  • Science Center, Tampere University Hospital, FI-33521, Tampere, Finland
  • 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.
  • Department of Public Health, Faculty of Medicine, University of Helsinki, FI-00014, Helsinki, Finland
  • Massachusetts General Hospital Weight Center, 02114, Boston, Massachusetts, USA
  • Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, SE-75185, Uppsala, Sweden
  • 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 and 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, LS2 9JT, Leeds, UK
  • Department of Medicine, Helsinki University Hospital, FI-00029, Helsinki, Finland
  • 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, 90095, Los Angeles, California, USA
  • Clinical Research Branch, National Institute on Aging, National Institutes of Health, 21225, Baltimore, Maryland, USA
  • Medizinische Klinik II, Universität zu Lübeck, 23538, Lübeck, Germany
  • MRC-HPA Centre for Environment and Health, Imperial College London, W2 1PG, London, UK
  • BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
  • Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177, Stockholm, Sweden
  • National Human Genome Research Institute, National Institutes of Health, 20892, Bethesda, Maryland, USA
  • Departments of Vascular Medicine & Cardiology, Academic Medical Centre, 1105 AZ, Amsterdam, The Netherlands
  • Department of Physiology and Biophysics, University of Southern California, 90033, Los Angeles, California, USA
  • Geriatric Unit, Azienda Sanitaria Firenze (ASF), 50125, Florence, Italy
  • Department of Medicine, Baylor College of Medicine, 77030, Houston, Texas, USA
  • Department of Medicine, Stanford University School of Medicine, 94305, Stanford, California, USA
  • Singapore Eye Research Institute, National University of Singapore, 168751, Singapore, Republic of Singapore
  • Departments of Medicine/Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Republic of Singapore
  • Office of Population Studies Foundation, University of San Carlos, 6000, Cebu City, Philippines
  • Department of Anthropology, Northwestern University, 60208, Evanston, Illinois, USA
  • Department of Nutrition, Carolina Population Center, University of North Carolina, 27516, Chapel Hill, North Carolina, USA
  • Department of Medicine, University of Mississippi Medical Center, 39126, Jackson, Mississippi, USA
  • Children’s Hospital Oakland Research Institute, 94609, Oakland, California, USA
  • Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Nutrition and Genomics Laboratory, 02111, Boston, Massachusetts, USA
  • 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.
  • Sage Bionetworks, 98109, Seattle, Washington, USA
  • Division of Community Health Sciences, St George’s University of London, SW17 0RE, London, UK
  • Department of Cardiovascular Sciences, University of Leicester, NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, LE3 9QP, Leicester, UK
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature09270

    DOI

    http://dx.doi.org/10.1038/nature09270

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1050402786

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/20686565


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