Article abstract


Nature Genetics 41, 56 - 65 (2008)
Published online: 7 December 2008 | Corrected online: 14 December 2008 | doi:10.1038/ng.291

Common variants at 30 loci contribute to polygenic dyslipidemia

Sekar Kathiresan1,2,3,4,5,37,38, Cristen J Willer6,37, Gina M Peloso4,7,37, Serkalem Demissie4,7,37, Kiran Musunuru1,2, Eric E Schadt8, Lee Kaplan9, Derrick Bennett10, Yun Li6, Toshiko Tanaka11, Benjamin F Voight2,3,12, Lori L Bonnycastle13, Anne U Jackson6, Gabriel Crawford3, Aarti Surti3, Candace Guiducci3, Noel P Burtt3, Sarah Parish10, Robert Clarke10, Diana Zelenika14, Kari A Kubalanza13, Mario A Morken13, Laura J Scott6, Heather M Stringham6, Pilar Galan15, Amy J Swift13, Johanna Kuusisto16, Richard N Bergman17, Jouko Sundvall18, Markku Laakso16, Luigi Ferrucci11, Paul Scheet6, Serena Sanna19, Manuela Uda19, Qiong Yang4,7, Kathryn L Lunetta4,7, Josée Dupuis4,7, Paul I W de Bakker20, Christopher J O'Donnell4,21, John C Chambers22, Jaspal S Kooner23, Serge Hercberg15, Pierre Meneton24, Edward G Lakatta25, Angelo Scuteri26, David Schlessinger27, Jaakko Tuomilehto18, Francis S Collins13, Leif Groop28,29, David Altshuler3,5,12,30, Rory Collins10, G Mark Lathrop14, Olle Melander31, Veikko Salomaa33, Leena Peltonen3,32,34, Marju Orho-Melander28, Jose M Ordovas35,38, Michael Boehnke6,38, Gonçalo R Abecasis6,38, Karen L Mohlke36,38 & L Adrienne Cupples4,7,38


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 < 5 times 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 < 10-15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Top
  1. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  3. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  4. Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA.
  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  6. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  7. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  8. Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle, Washington 98109, USA.
  9. Massachusetts General Hospital Weight Center, Boston, Massachusetts 02114, USA.
  10. Clinical Trial Service Unit, University of Oxford, Oxford OX3 7LF, UK.
  11. Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.
  12. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  13. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  14. Centre Nationale de Genotypage, Institut Genomique, Commissariat a l'Energie Atomique, Evry Cedex 91057, France.
  15. INSERM U557, INRA U1125, CNAM, Paris 13 SMBH, Bobigny, France.
  16. Department of Medicine, University of Kuopio, Kuopio 70210, Finland.
  17. Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
  18. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki 00300, Finland.
  19. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 08045, Italy.
  20. Division of Genetics, Bringham and Women's Hospital, Boston, Massachusetts 02115, USA.
  21. National, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts 01702, USA.
  22. Department of Epidemiology and Public Health, Imperial College London, London W2 1PG, UK.
  23. Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
  24. INSERM U872, Centre de Recherche des Cordeliers, 75270 Paris Cedex 06, France.
  25. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  26. Unità Operativa Geriatria, Istituto Nazionale Ricovero e Cura per Anziani, 00189 Rome, Italy.
  27. Laboratory of Genetics, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  28. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö 20502, Sweden.
  29. Department of Medicine, Helsinki University Hospital, Helsinki 00029, Finland.
  30. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115,USA.
  31. Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö 20502, Sweden.
  32. Institute for Molecular Medicine, University of Helsinki, Helsinki 00029, Finland.
  33. Chronic Disease Epidemiology Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki 00300, Finland.
  34. Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  35. Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.
  36. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
  37. These authors contributed equally to this work.
  38. These authors contributed equally to this work.

Correspondence to: Sekar Kathiresan1,2,3,4,5,37,38 e-mail: skathiresan@partners.org

Correspondence to: Gonçalo R Abecasis6,38 e-mail: goncalo@umich.edu

Correspondence to: Karen L Mohlke36,38 e-mail: mohlke@med.unc.edu

Correspondence to: L Adrienne Cupples4,7,38 e-mail: adrienne@bu.edu

* NOTE: In the version of this article initially published online, Paul I.W. de Bakker?s name was misspelled in the author list. The error has been corrected for all versions of this article.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.

NEWS AND VIEWS

A treasure trove for lipoprotein biology

Nature Genetics News and Views (01 Feb 2008)

Genomics Variations in blood lipids

Nature News and Views (05 Aug 2010)

See all 4 matches for News And Views