Detecting Epistasis in Genome-wide Association Studies with the Marginal EPIstasis Test

Epistasis, commonly defined as the interaction between multiple genes, is an important genetic component underlying phenotypic variation. Many statistical methods have been developed to model and identify epistatic interactions between genetic variants. However, because of the large combinatorial search space of interactions, most epistasis mapping methods face enormous computational challenges and often suffer from low statistical power. Here, we present a novel, alternative strategy for mapping epistasis: instead of directly identifying individual pairwise or higher-order interactions, we focus on mapping variants that have non-zero marginal epistatic effects — the combined pairwise interaction effects between the given variant and all other variants. By testing marginal epistatic effects, we can identify candidate variants that are involved in epistasis without the need to identify the exact partners with which the variants interact, thus potentially alleviating much of the statistical and computational burden associated with standard epistatic mapping procedures. Our method is based on the variance component model, and relies on a recently developed variance component estimation method for efficient parameter inference and p-value computation. We refer to our method as the “Marginal EPIstasis Test”, or MEPIT. With simulations, we show how MEPIT can be used to robustly estimate marginal epistatic effects, produce calibrated test statistics under the null, and facilitate the detection of pairwise epistatic interactions. We further illustrate the benefits of MEPIT on several real datasets, including seven common diseases from the Wellcome Trust Case Control Consortium, as well as body composition traits from a swine genome-wide association study.