RT Journal Article SR Electronic T1 Epistasis within the MHC contributes to the genetic architecture of celiac disease JF bioRxiv FD Cold Spring Harbor Laboratory SP 002485 DO 10.1101/002485 A1 Benjamin Goudey A1 Gad Abraham A1 Eder Kikianty A1 Qiao Wang A1 Dave Rawlinson A1 Fan Shi A1 Izhak Haviv A1 Linda Stern A1 Adam Kowalczyk A1 Michael Inouye YR 2014 UL http://biorxiv.org/content/early/2014/05/29/002485.abstract AB 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.