Common variants at 30 loci contribute to polygenic dyslipidemia

Nat Genet. 2009 Jan;41(1):56-65. doi: 10.1038/ng.291. Epub 2008 Dec 7.

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 < 5 x 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Dyslipidemias / blood
  • Dyslipidemias / genetics*
  • Female
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Humans
  • Liver / metabolism
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Multifactorial Inheritance / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Syndrome
  • Triglycerides / blood

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • RNA, Messenger
  • Triglycerides