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

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.

Figure 1. Rare variants identified by resequencing GWAS-identified genes in HTG patients and controls

Variants above gene maps were identified in HTG patients and variants below gene maps were identified in controls. Rare variants are coloured according to their identification in control subjects or previous identification in subjects of unknown clinical status (black), exclusivity to HTG patients or controls (blue), or proven biological dysfunction or truncation (red). Nomenclature refers to functional protein sequences. Only exons 26 and 29 were resequenced in APOB. Gene maps are roughly to scale, although differ in scale between genes. GWAS, genome-wide association study; HTG, hypertriglyceridemia; TG, triglyceride.