Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia Journal Articles uri icon

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  • 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.


  • Johansen, Christopher
  • Wang, Jian
  • Lanktree, Matthew
  • Cao, Henian
  • McIntyre, Adam D
  • Ban, Matthew R
  • Martins, Rebecca A
  • Kennedy, Brooke A
  • Hassell, Reina G
  • Visser, Maartje E
  • Schwartz, Stephen M
  • Voight, Benjamin F
  • Elosua, Roberto
  • Salomaa, Veikko
  • O'Donnell, Christopher J
  • Dallinga-Thie, Geesje M
  • Anand, Sonia
  • Yusuf, Salim
  • Huff, Murray W
  • Kathiresan, Sekar
  • Hegele, Robert A

publication date

  • August 2010