A systematic analysis of IBD GWAS loci identifies most probable causal genes impacting intestinal epithelial functions
TL;DR
Combining multiple genetic, genomic, and functional data is a useful approach for prioritizing the most likely causal gene within IBD GWAS loci, and for prioritizing functional validation studies in epithelial cells and tissues.
Abstract
Background Genome-wide association studies have identified >200 loci associated with IBD, yet the causal gene for most remains unknown. As multiple epithelial functions have been linked with susceptibility to IBD, there is a need to prioritize candidate causal genes for functional studies in this cellular context. Methods Using a standardized definition of regions implicated by index SNPs from three GWAS studies, we categorized regions as containing: (1) a known casual gene, (2) a single gene or (3) multiple genes. We then developed an IBD Priority Score to rank genes based on genetic, genomic and functional data. We next developed and applied an Epithelial Priority Score, based on expression patterns and quantitative traits, to prioritize genes for functional validation in epithelial models. Two candidate genes identified through this approach were tested for their impact on viral response pathways in HT-29 cells. Results The IBD Priority Score prioritized a single gene in 71 of the 104 regions containing multiple genes. The Epithelial Priority Score identified 31 epithelial candidates. Functional studies demonstrated that IRF6 enhanced, whereas IRF8 suppressed, antiviral responses in intestinal epithelial cells stimulated with Poly(I:C). Conclusions Combining multiple genetic, genomic, and functional data is a useful approach for prioritizing the most likely causal gene within IBD GWAS loci, and for prioritizing functional validation studies in epithelial cells and tissues. Moreover, we provide functional evidence for two IBD genes playing a role in the regulation of anti-viral responses in intestinal epithelial cells.