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

Abstract

Robert Hegele and colleagues report a genome-wide association study for hypertriglyceridemia, followed by resequencing of the coding regions of candidate genes. They identify an excess of rare variants in affected individuals at four genes within the associated loci. Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations1,2,3,4,5. Common variants at these loci together explain <10% of variation in each lipid trait4,5. Rare variants with large individual effects may also contribute to the heritability of lipid traits6,7; 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 × 10−8), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 × 10−5). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.