title: Interactions within the MHC contribute to the genetic architecture of celiac disease.
abstract: Interaction analysis of GWAS can detect signal that would be ignored by single variant analysis, yet few robust interactions in humans have been detected. Recent work has highlighted interactions in the MHC region between known HLA risk haplotypes for various autoimmune diseases. To better understand the genetic interactions underlying celiac disease (CD), we have conducted exhaustive genome-wide scans for pairwise interactions in five independent CD case-control studies, using a rapid model-free approach to examine over 500 billion SNP pairs in total. We found 14 independent interaction signals within the MHC region that achieved stringent replication criteria across multiple studies and were independent of known CD risk HLA haplotypes. The strongest independent CD interaction signal corresponded to genes 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 statistical interaction outside the MHC was not observed. Both within and between European populations, we observed striking consistency of two-locus models and model distribution. Within the UK population, models of CD based on both interactions and additive single-SNP effects increased explained CD variance by approximately 1% over those of single SNPs. The interactions signal detected across the five cohorts indicates the presence of novel associations in the MHC region that cannot be detected using additive models. Our findings have implications for the determination of genetic architecture and, by extension, the use of human genetics for validation of therapeutic targets.
authors.affiliation: NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria, Australia.|Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.|Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria, Australia.|IBM Research, Australia, Level 5, Carlton, Victoria, Australia.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0002-2318-985X
authors.initials: B
authors.lastname: Goudey
authors.affiliation: Centre for Systems Genomics, The University of Melbourne, Parkville, Victoria, Australia.|School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia.|Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gad
authors.initials: G
authors.lastname: Abraham
authors.affiliation: Department of Mathematics, University of Johannesburg, Auckland Park, South Africa.
authors.forename: Eder
authors.initials: E
authors.lastname: Kikianty
authors.affiliation: NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria, Australia.|Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria, Australia.|Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Dave
authors.initials: D
authors.lastname: Rawlinson
authors.affiliation: NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria, Australia.|Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Fan
authors.initials: F
authors.lastname: Shi
authors.affiliation: Faculty of Medicine, Bar Ilan University, Safed, Israel.
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Stern
authors.affiliation: NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria, Australia.|Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.|Center for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: Centre for Systems Genomics, The University of Melbourne, Parkville, Victoria, Australia.|School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia.|Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
mesh_terms: D000483:Alleles; D019540:Area Under Curve; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D012372:ROC Curve; D012306:Risk; D060388:Support Vector Machine
chemical_list: D011506:Proteins; C092008:PRRC2A protein, human