Common variants at 30 loci contribute to polygenic dyslipidemia

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  • Kathiresan, Sekar
    • Other Affiliation: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • Willer, Cristen J.
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA
  • Peloso, Gina M.
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA
  • Demissie, Serkalem
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  • Musunuru, Kiran
    • Other Affiliation: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • Schadt, Eric E.
    • Other Affiliation: Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle, Washington 98109, USA.
  • Kaplan, Lee
    • Other Affiliation: Massachusetts General Hospital Weight Center, Boston, Massachusetts 02114, USA.
  • Bennett, Derrick
    • Other Affiliation: Clinical Trial Service Unit, University of Oxford, Oxford OX3 7LF, UK.
  • Li, Yun
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Tanaka, Toshiko
    • Other Affiliation: Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.
  • Voight, Benjamin F.
    • Other Affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • Bonnycastle, Lori L.
    • Other Affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Jackson, Anne U.
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Crawford, Gabriel
    • Other Affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  • Surti, Aarti
    • Other Affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  • Guiducci, Candace
    • Other Affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  • Burtt, Noel P.
    • Other Affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  • Parish, Sarah
    • Other Affiliation: Clinical Trial Service Unit, University of Oxford, Oxford OX3 7LF, UK.
  • Clarke, Robert
    • Other Affiliation: Clinical Trial Service Unit, University of Oxford, Oxford OX3 7LF, UK.
  • Zelenika, Diana
    • Other Affiliation: Centre Nationale de Genotypage, Institut Genomique, Commissariat a l'Energie Atomique, Evry Cedex 91057, France.
  • Kubalanza, Kari A.
    • Other Affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Morken, Mario A.
    • Other Affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Scott, Laura J.
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Stringham, Heather M.
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Galan, Pilar
    • Other Affiliation: INSERM U557, INRA U1125, CNAM, Paris 13 SMBH, Bobigny, France.
  • Swift, Amy J.
    • Other Affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Kuusisto, Johanna
    • Other Affiliation: Department of Medicine, University of Kuopio, Kuopio 70210, Finland.
  • Bergman, Richard N.
    • Other Affiliation: Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
  • Sundvall, Jouko
    • Other Affiliation: Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki 00300, Finland.
  • Laakso, Markku
    • Other Affiliation: Department of Medicine, University of Kuopio, Kuopio 70210, Finland.
  • Ferrucci, Luigi
    • Other Affiliation: Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.
  • Scheet, Paul
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Sanna, Serena
    • Other Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 08045, Italy.
  • Uda, Manuela
    • Other Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 08045, Italy.
  • Yang, Qiong
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  • Lunetta, Kathryn L.
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  • Dupuis, Josée
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  • de Bakker, Paul I. W.
    • Other Affiliation: Division of Genetics, Bringham and Women's Hospital, Boston, Massachusetts 02115, USA.
  • O'Donnell, Christopher J.
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. National, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts 01702, USA.
  • Chambers, John C.
    • Other Affiliation: Department of Epidemiology and Public Health, Imperial College London, London W2 1PG, UK.
  • Kooner, Jaspal S.
    • Other Affiliation: Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
  • Hercberg, Serge
    • Other Affiliation: INSERM U557, INRA U1125, CNAM, Paris 13 SMBH, Bobigny, France.
  • Meneton, Pierre
    • Other Affiliation: INSERM U872, Centre de Recherche des Cordeliers, 75270 Paris Cedex 06, France.
  • Lakatta, Edward G.
    • Other Affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  • Scuteri, Angelo
    • Other Affiliation: Unità Operativa Geriatria, Istituto Nazionale Ricovero e Cura per Anziani, 00189 Rome, Italy.
  • Schlessinger, David
    • Other Affiliation: Laboratory of Genetics, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  • Tuomilehto, Jaakko
    • Other Affiliation: Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki 00300, Finland.
  • Collins, Francis S.
    • Other Affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Groop, Leif
    • Other Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö 20502, Sweden. Department of Medicine, Helsinki University Hospital, Helsinki 00029, Finland.
  • Altshuler, David
    • Other Affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115,USA.
  • Collins, Rory
    • Other Affiliation: Clinical Trial Service Unit, University of Oxford, Oxford OX3 7LF, UK.
  • Lathrop, G. Mark
    • Other Affiliation: Centre Nationale de Genotypage, Institut Genomique, Commissariat a l'Energie Atomique, Evry Cedex 91057, France.
  • Melander, Olle
    • Other Affiliation: Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö 20502, Sweden.
  • Salomaa, Veikko
    • Other Affiliation: Chronic Disease Epidemiology Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki 00300, Finland.
  • Peltonen, Leena
    • Other Affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. Institute for Molecular Medicine, University of Helsinki, Helsinki 00029, Finland. Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  • Orho-Melander, Marju
    • Other Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö 20502, Sweden.
  • Ordovas, Jose M.
    • Other Affiliation: Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.
  • Boehnke, Michael
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Abecasis, Gonçalo R.
    • Other Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Mohlke, Karen
    • Affiliation: School of Medicine, Department of Genetics
  • Cupples, L. Adrienne
    • Other Affiliation: Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Abstract
  • Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P less than 5 × 10−8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P less than 10−15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Nature Genetics
Journal volume
  • 41
Journal issue
  • 1
Page start
  • 56
Page end
  • 65
Language
  • English
Version
  • Postprint
ISSN
  • 1061-4036

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