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Epistasis within the MHC contributes to the genetic architecture of celiac disease

Benjamin Goudey, Gad Abraham, Eder Kikianty, Qiao Wang, Dave Rawlinson, Fan Shi, Izhak Haviv, Linda Stern, Adam Kowalczyk, Michael Inouye
doi: https://doi.org/10.1101/002485
Benjamin Goudey
1NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria 3010, Australia
2Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
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Gad Abraham
3Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia
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Eder Kikianty
4Department of Mathematics, University of Johannesburg, PO Box 524, Auckland Park 2006, South Africa
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Qiao Wang
1NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria 3010, Australia
2Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
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Dave Rawlinson
1NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria 3010, Australia
2Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
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Fan Shi
1NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria 3010, Australia
2Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
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Izhak Haviv
5Bar Ilan University, Safed, Israel
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Linda Stern
2Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
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Adam Kowalczyk
1NICTA Victoria Research Lab, The University of Melbourne, Parkville, Victoria 3010, Australia
2Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
6Center for Neural Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
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Michael Inouye
3Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia
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Abstract

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.

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Posted May 29, 2014.
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Epistasis within the MHC contributes to the genetic architecture of celiac disease
Benjamin Goudey, Gad Abraham, Eder Kikianty, Qiao Wang, Dave Rawlinson, Fan Shi, Izhak Haviv, Linda Stern, Adam Kowalczyk, Michael Inouye
bioRxiv 002485; doi: https://doi.org/10.1101/002485
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Epistasis within the MHC contributes to the genetic architecture of celiac disease
Benjamin Goudey, Gad Abraham, Eder Kikianty, Qiao Wang, Dave Rawlinson, Fan Shi, Izhak Haviv, Linda Stern, Adam Kowalczyk, Michael Inouye
bioRxiv 002485; doi: https://doi.org/10.1101/002485

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