From Locus Association to Mechanism of Gene Causality

Arguably, one of the greatest advances in biomedical research in the past decades has been the association of human allelic variation with complex human diseases and phenotypes. Certainly, initially these findings were met with skepticism, given the underpowered and misleading number of candidate gene association studies that preceded the genome-wide association (GWA) era. Also, there was considerable incredulity when it became clear that identified variation in reasonably powered GWA studies (GWAS) could not address the bulk of attributable genetic risk for the majority of diseases. However, scientists in academia and industry are now increasingly recognizing the importance of studying these loci for better understanding of disease pathways and developing new therapeutics. This is perhaps most significant for atherosclerotic coronary artery disease (CAD), the primary source of mortality and morbidity worldwide, for which no single drug has yet been developed to target the primary disease process in the vessel wall.See accompanying article on page 2207 GWAS have identified common variation throughout the genome that associates with specific diseases, but these single-nucleotide polymorphisms (SNPs) provide little information about the mechanism for this association. Lead variants reported in GWAS are commonly tag SNPs chosen to represent regions of linkage disequilibrium (LD) that can be hundreds of thousands of nucleotides in length. The next era of GWAS will be focused on finding the causal variation in these loci, using this information to identify the causal gene, and then elucidating the mechanisms behind disease risk susceptibility. Deciphering precise molecular mechanisms will involve both state-of-the-art computational analysis and in vitro and in …