Tackling the role of rare functional variation in inflammatory bowel disease through application of GenePy2 as a potential DNA biomarker

Abstract Rare and common variants often converge in the pathogenic pathway of in inflammatory bowel disease (IBD), a heterogenous autoimmune condition with genomic and environmental influences. We identified 794 functionally-targeted-genes/linkage-disequilibrium-mapped blocks (LDBs) implicated by genome-wide-association-studies (GWAS), then developed GenePy2, a burden score that integrates functional impacts of rare variants for each gene/LDB, using exome data of UK-Biobank phase2 IBD cohort. Through case/control 2-way Man-Whitney-U test tuning on subpopulations with extreme GenePy2 scores, 34 genes/LDBs in Crohn’s disease (CD) and 25 in Ulcerative Colitis (UC) survived significance test, confirming roles for rare functional variants. The optimal threshold of GenePy2 were then pinpointed for each gene/LDB based on tests’ maximum effect size. Further itemset association mining of the binarised GenePy2 scores detected an intriguing cooccurrence of extreme scores of the risk NOD2 and protective IL23R in controls, which are mutually exclusive in CD patients, implicating a ‘rescue’ of disease by protective rare variants.