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

Abstract

Genome-wide association studies (GWAS) have replicably identified multiple loci associated with population-based plasma lipid concentrations1-5. Common genetic variants at these loci together explain <10% of the total variation of each lipid trait4,5. Rare variants of individually large effect may contribute additionally to the “missing heritability” of lipid traits6,7, however it remains to be shown to what extent rare variants will affect lipid phenotypes. Here, we demonstrate a significant accumulation of rare variants in GWAS-identified genes in patients with an extreme phenotype of abnormal plasma triglyceride (TG) metabolism. A GWAS of hypertriglyceridemia (HTG) patients revealed that common variants in APOA5, GCKR, LPL and APOB genes were associated with the HTG phenotype at genome-wide significance. We subsequently resequenced protein coding regions of these genes and found a significant burden of 154 rare missense or nonsense variants in 438 HTG patients, in contrast to 53 variants in 327 controls (P=6.2X10-8); this corresponds to a carrier frequency of 28.1% of HTG patients and 15.3% of controls (P=2.6X10-5). Many rare variants were predicted in silico to have compromised function; additionally some had previously demonstrated dysfunctionality in vitro. Rare variants in these 4 genes explained 1.1% of total variation in HTG diagnoses. Our study demonstrates a marked mutation skew that likely contributes to disease pathophysiology in patients with HTG.

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…One of the variants, p.Arg3527Gln, is a well-characterized pathogenic missense variant [67] in APOB, and was identified in only one heterozygous individual among the 2049 individuals (allele frequency = 0.0002). Another missense variant, p. Ile3768Thr [68], was registered as DM in HGMD, and was identified in 2KJPN in a heterozygous individual. However, no evidence for the pathogenicity of this variant has been presented; therefore, its clinical and functional significance must be scrutinized.…”

Inferring causality and functional significance of human coding DNA variants

“…A number of successful candidate gene sequencing studies discovered associations of multiple rare coding variants with complex phenotypes (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Ongoing whole-exome sequencing studies attempt an unbiased search for genes harboring multiple rare variants collectively associated with complex traits (33).…”

A model of compound heterozygous, loss-of-function alleles is broadly consistent with observations from complex-disease GWAS datasets

“…From an empirical perspective, our findings suggest that re-sequencing in large samples is likely the best way forward in the face of the allelic heterogeneity imposed by the presence of rare alleles of large effect. Resequencing of candidate genes [77][78][79][80] and exomes [40,[81][82][83][84][85][86] in case-control panels have observed an abundance of rare variants associated with case status. Here we show that under a model of mutation-selection balance on the genic level, neither current single-marker nor popular multi-marker tests are especially powerful at detecting large genomic regions harboring multiple risk variants (Fig 3).…”