Study of Exonic Variation Identifies Incremental Information Regarding Lipid-Related and Coronary Heart Disease Genes
Recently, a modest-sized population-based study of exonic variants facilitated the identification of the causal gene, TM6SF2, in a gene-rich locus on 19p1 previously associated with cholesterol levels in blood. The study also provided compelling functional validation of the locus and evidence at the population level that interference with the function of this gene may substantially reduce the risk of coronary artery disease. The study highlights the potential utility of large-scale studies of coding variants but also hints toward the need of much larger studies to provide insight at other loci. Conducting such studies in parallel with association studies of variation in well-annotated regulatory regions is likely to ultimately yield the highest returns.
Genome-wide association studies (GWAS) conducted over the past decade have identified many regions of the genome harboring common susceptibility variants for complex traits.1 For many traits, the overall proportion of the genetic variance explained by GWAS to date remains modest.2 A few exceptions exist including blood levels of lipids where large meta-analyses have successfully identified >150 loci for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides.3,4 Remarkably, these discoveries seem to explain more than one quarter of the genetic variance of each trait.3,4
A majority of these GWAS loci are novel and have not been previously linked to lipid biology.3,4 For many, the lead single-nucleotide polymorphism (SNP) falls in noncoding regions of the genome and the association interval stretches over several kilobases often overlapping several candidate genes.3,4 This situation makes it extremely challenging to determine the causal gene. Several population genetic approaches can be used to help identify the causal gene. First, one can examine the same risk interval in multiple racial groups with the hope that differences in linkage …