Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

Abstract

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

IL-23R–activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity

“…This analysis was performed on total memory CD4 T cells, not myelin-specific T cells, suggesting that MS patients may inherently be more responsive to IL-23, which suggests that IL-23R may be a susceptibility factor. IL-23R polymorphism is associated with multiple autoimmune diseases (58)(59)(60), but it has not yet shown a significant correlation with MS risk. An alternative hypothesis is that the inflammatory process in MS may enhance IL-23R sensitivity and perhaps contribute to exacerbation rates or disease progression.…”

Pathophysiology of Functional Gastrointestinal Disorders: A Holistic Overview

“…The largest genome-wide association study to date in IBS contained only around 5,500 individuals [38], which compared with 30 to 40,000 in some inflammatory bowel disease cohorts [39, 40], limits the ability to draw firm conclusions.…”

Systems biology in inflammatory bowel diseases

“…Previous studies have revealed the significance of genetic variations in IBD pathogenesis by performing large genome-wide association studies (GWAS) 17 . However, the genetic variants that have been associated with UC and CD can only explain the 20-25% of all IBD cases, suggesting the presence of additional contributing factors 18 .…”