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

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

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  • 1Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.

Abstract

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.

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PMID:
20657596
[PubMed - indexed for MEDLINE]
PMCID:
PMC3017369
Free PMC Article

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