Epistasis associated to inflammatory bowel disease (IBD) in humans

Gene-gene interactions underlie biochemical pathways and have been well demonstrated in model organisms. Very few examples exist on replicated epistasis in humans. Here, we performed genome-wide scans to detect epistasis associated to Crohn’s disease (CD) and ulcerative colitis (UC). We used extensive data of the IIBDGC consisting of 18277 and 14224 CD and UC patients, respectively, and ~34050 healthy controls from 15 European countries typed on the Immunochip. At first, we removed rare variants at MAF<0.05 and filtered common variants at linkage disequilibrium (LD) of r2>0.75. To limit our results to independent effects, SNPs on chromosome 6 (which contains the HLA locus), were furthermore pruned to ensure an LD of r2<0.35. We adjusted the binary traits, CD and UC, for population stratification by regressing out the first 5 principal components in R-3.0.1. The study cohorts were randomly stratified into two subgroups (referred as discovery and replication). We then performed screenings for epistatic interactions with new adjusted trait values in the two subgroups using multidimensional reduction tool MB-MDR with permutation-based (step-down MaxT) multiple testing correction and significance assessment at 0.05. We identified 14 and 6 SNP-pairs associated to CD and UC, respectively, which were concordant between the discovery and replication groups. All SNP-pairs involved concomitant variants located on the same chromosomes (for CD at 1p31.3, 5p13.1, 16q12.1 and for UC at 1p31.3, 6p21.3). A more detailed investigation of these findings, as well as the implementation of different analysis protocols, will further increase our understanding of possible epistatic mechanisms underpinning IBD.