Alexandra Fish, John A. Capra, William S Bush
Interactions between genetic variants, also called epistasis, are pervasive in model organisms; however, their importance in humans remains unclear because statistical interactions in observational studies can be explained by processes other than biological epistasis. Using statistical modeling, we identified 1,093 interactions between pairs of cis-regulatory variants impacting gene expression in lymphoblastoid cell lines. Factors known to confound these analyses (ceiling/floor effects, population stratification, haplotype effects, or single variants tagged through linkage disequilibrium) explained most of these interactions. However, we found 15 interactions robust to these explanations, and we further show that despite potential confounding, interacting variants were enriched in numerous regulatory regions suggesting potential biological importance. While genetic interactions may not be the true underlying mechanism of all our statistical models, our analyses discover new signals undetected in standard single-marker analyses. Ultimately, we identified new complex genetic architectures regulating 23 genes, suggesting that single-variant analyses may miss important modifiers.