A General Model for Multilocus Epistatic Interactions in Case-Control Studies

BACKGROUND Epistasis, i.e., the interaction of alleles at different loci, is thought to play a central role in the formation and progression of complex diseases. The complexity of disease expression should arise from a complex network of epistatic interactions involving multiple genes. METHODOLOGY We develop a general model for testing high-order epistatic interactions for a complex disease in a case-control study. We incorporate the quantitative genetic theory of high-order epistasis into the setting of cases and controls sampled from a natural population. The new model allows the identification and testing of epistasis and its various genetic components. CONCLUSIONS Simulation studies were used to examine the power and false positive rates of the model under different sampling strategies. The model was used to detect epistasis in a case-control study of inflammatory bowel disease, in which five SNPs at a candidate gene were typed, leading to the identification of a significant three-locus epistasis.