Multiple epistasis interactions within MHC are associated with ulcerative colitis

Successful searching for epistasis is much challenging, which generally requires very large sample sizes and/or very dense marker information. We exploited the largest Crohn's disease (CD) dataset (18,000 cases + 34,000 controls) and ulcerative colitis (UC) dataset (14,000 cases + 34,000 controls) to date. Leveraging its dense marker information and the large sample size of this IBD dataset, we employed a two-step approach to exhaustively search for epistasis. We detected abundant genome-wide significant (p < 1 × 10⁻¹³) epistatic signals, all within the MHC region. These signals were reduced substantially when conditional on the additive background, but still nine pairs remained significant at the Immunochip-wide level (P < 1.1 × 10⁻⁸) in conditional tests for UC. All these nine epistatic interactions come from the MHC region, and each explains on average 0.15% of the phenotypic variance. Eight of them were replicated in a replication cohort. There are multiple but relatively weak interactions independent of the additive effects within the MHC region for UC. Our promising results warrant the search for epistasis in large data sets with dense markers, exploiting dependencies between markers.