TY - JOUR T1 - Epistasis within the MHC contributes to the genetic architecture of celiac disease JF - bioRxiv DO - 10.1101/002485 SP - 002485 AU - Benjamin Goudey AU - Gad Abraham AU - Eder Kikianty AU - Qiao Wang AU - Dave Rawlinson AU - Fan Shi AU - Izhak Haviv AU - Linda Stern AU - Adam Kowalczyk AU - Michael Inouye Y1 - 2014/01/01 UR - http://biorxiv.org/content/early/2014/05/29/002485.abstract N2 - Epistasis has long been thought to contribute to the genetic aetiology of complex diseases, yet few robust epistatic interactions in humans have been detected. We have conducted exhaustive genome-wide scans for pairwise epistasis in five independent celiac disease (CD) case-control studies, using a rapid model-free approach to examine over 500 billion SNP pairs in total. We found 5,359 significant epistatic pairs within the HLA region which achieved stringent replication criteria across multiple studies. These pairs comprised 20 independent epistatic signals which were also independent of known CD risk HLA haplotypes. The strongest independent CD epistatic signal corresponded to variants in the HLA class III region, in particular PRRC2A and GPANK1/C6orf47 which are known to contain variants for non-Hodgkin’s lymphoma and early menopause, co-morbidities of celiac disease. Replicable evidence for epistatic variants outside the MHC was not observed. Both within and between European populations, we observed striking consistency of epistatic models and epistatic model distribution. Within the UK population, models of CD based on both epistatic and additive single-SNP effects increased explained CD variance by approximately 1% over those of single SNPs. Models of only epistatic pairs or additive single-SNPs showed similar levels of CD variance explained, indicating the existence of a substantial overlap of additive and epistatic components. ER -