Common variants at 30 loci contribute to polygenic dyslipidemia

Sekar Kathiresan, Cristen J. Willer, Gina M. Peloso, Serkalem Demissie, Kiran Musunuru, Eric E. Schadt, Lee Kaplan, Derrick Bennett, Yun Li, Toshiko Tanaka, Benjamin F. Voight, Lori L. Bonnycastle, Anne U. Jackson, Gabriel Crawford, Aarti Surti, Candace Guiducci, Noel P. Burtt, Sarah Parish, Robert Clarke, Diana ZelenikaKari A. Kubalanza, Mario A. Morken, Laura J. Scott, Heather M. Stringham, Pilar Galan, Amy J. Swift, Johanna Kuusisto, Richard N. Bergman, Jouko Sundvall, Markku Laakso, Luigi Ferrucci, Paul Scheet, Serena Sanna, Manuela Uda, Qiong Yang, Kathryn L. Lunetta, Josée Dupuis, Paul I.W. De Bakker, Christopher J. O'Donnell, John C. Chambers, Jaspal S. Kooner, Serge Hercberg, Pierre Meneton, Edward G. Lakatta, Angelo Scuteri, David Schlessinger, Jaakko Tuomilehto, Francis S. Collins, Leif Groop, David Altshuler, Rory Collins, G. Mark Lathrop, Olle Melander, Veikko Salomaa, Leena Peltonen, Marju Orho-Melander, Jose M. Ordovas, Michael Boehnke, Gonçalo R. Abecasis, Karen L. Mohlke, L. Adrienne Cupples

Research output: Contribution to journalArticlepeer-review

1121 Scopus citations


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 × 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.

Original languageEnglish
Pages (from-to)56-65
Number of pages10
JournalNature Genetics
Issue number1
StatePublished - Jan 2009
Externally publishedYes


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