Li Y, Cho H, Wang F, et al. - Given that epistasis defines how gene‐gene interactions influence phenotypes, and could exert a profound effect on human diseases such as coronary artery disease (CAD), so, researchers investigated gene‐gene interactions in CAD by employing an easily generalizable multi‐stage approach. Upregulation of TMEM100 and TMEM106B due to knockdown of ANRIL (DQ485454) at 9p21.3 GWAS (genome‐wide association studies) CAD locus was shown in global gene expression profiling. As per functional studies, knockdown of TMEM106B, but not of TMEM100 led to the reversal of increased monocyte adhesion to endothelial cells and transendothelial migration of monocytes, 2 important processes in the CAD initiation, by ANRIL knockdown. A significant link was identified between variants in TMEM106B (but not in TMEM100) and CAD. Overall, 2 pairs of epistatic interactions between GWAS loci for CAD were shown in this study, and the observations afford crucial insights into the genetic architecture as well as molecular mechanisms for the pathogenesis of CAD. Experts' strategy holds wide applicability to the detection of epistasis in other human diseases.