Common variants at 30 loci contribute to polygenic dyslipidemia

• Published in: Nature genetics Vol. 41; no. 1; pp. 56 - 65
• Main Authors: Kooner, Jaspal S, Mohlke, Karen L, Groop, Leif, Schadt, Eric E, O'Donnell, Christopher J, Zelenika, Diana, Sanna, Serena, Bonnycastle, Lori L, Yang, Qiong, Hercberg, Serge, Schlessinger, David, Chambers, John C, Laakso, Markku, Li, Yun, Ordovas, Jose M, Ferrucci, Luigi, Orho-Melander, Marju, Surti, Aarti, de Bakker, Paul I W, Clarke, Robert, Kathiresan, Sekar, Tanaka, Toshiko, Stringham, Heather M, Salomaa, Veikko, Willer, Cristen J, Scott, Laura J, Tuomilehto, Jaakko, Swift, Amy J, Lathrop, G Mark, Melander, Olle, Collins, Rory, Dupuis, Josée, Collins, Francis S, Lunetta, Kathryn L, Jackson, Anne U, Galan, Pilar, Peltonen, Leena, Peloso, Gina M, Musunuru, Kiran, Kuusisto, Johanna, Sundvall, Jouko, Crawford, Gabriel, Guiducci, Candace, Meneton, Pierre, Lakatta, Edward G, Altshuler, David, Scheet, Paul, Burtt, Noel P, Kaplan, Lee, Abecasis, Gonçalo R, Parish, Sarah, Uda, Manuela, Kubalanza, Kari A, Scuteri, Angelo, Boehnke, Michael, Voight, Benjamin F, Cupples, L Adrienne, Demissie, Serkalem, Bennett, Derrick, Bergman, Richard N, Morken, Mario A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2009; Nature Publishing Group
• Subjects: Adult; Agriculture; Alleles; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiac and Cardiovascular Systems; Cardiovascular diseases; Cholesterol; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Clinical Medicine; Delta-5 Fatty Acid Desaturase; Dyslipidemias; Dyslipidemias - blood; Dyslipidemias - genetics; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Gene Function; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Health aspects; Human Genetics; Humans; Kardiologi; Klinisk medicin; Liver - metabolism; Male; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Meta-Analysis as Topic; Middle Aged; Multifactorial Inheritance - genetics; Phenotype; Polymorphism, Single Nucleotide - genetics; Quantitative Trait Loci - genetics; Reproducibility of Results; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Single nucleotide polymorphisms; Studies; Syndrome; Triglycerides - blood; United States; United Kingdom; Variant; Metabolic diseases; Lipids; Dyslipemia; Locus; Polygenic
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.291

Sekar Kathiresan et al . report genome-wide association studies for polygenic dyslipidemia. From a meta-analysis of seven genome-wide association studies and follow-up in five replication studies, they identify 11 new genetic associations for LDL cholesterol, HDL cholesterol and triglycerides. 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.