Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia

Nat Genet. 2010 Aug;42(8):684-7. doi: 10.1038/ng.628. Epub 2010 Jul 25.


Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Apolipoprotein A-V
  • Apolipoproteins A
  • Cohort Studies
  • Female
  • Genes
  • Genetic Testing
  • Genetic Variation
  • Genome-Wide Association Study*
  • Humans
  • Hypertriglyceridemia / genetics*
  • Lipids / blood*
  • Lipids / genetics*
  • Lipoprotein Lipase
  • Male
  • Middle Aged
  • Phenotype


  • APOA5 protein, human
  • Adaptor Proteins, Signal Transducing
  • Apolipoprotein A-V
  • Apolipoproteins A
  • GCKR protein, human
  • Lipids
  • Lipoprotein Lipase