DOP051Exome-wide Association Study Reveals Novel Genetic Risk Loci for Inflammatory Bowel Disease

Abstract Background While more than 300 common genomic loci have been identified to be associated with inflammatory bowel disease (IBD), the effect of rare and protein coding variants remain unexplored. Methods Whole-exome sequencing data from 365,847 unrelated individuals of European ancestry in the UK Biobank were included. Gene-based analyses were conducted focusing on rare predicted loss-of-function and likely pathogenic missense variants across 16,879 protein-coding genes. In parallel, common coding variants were evaluated through single-variant analysis. Risk stratification was assessed by integrating polygenic risk scores (PRS) with rare variant carrier status. Causal inference, expression enrichment, functional annotation, and druggability assessment were integrated to enhance interpretation (Figure 1). Results Gene-based analyses identified six genes associated with IBD, including novel finding associations with SPON2, NOMO2, BCAR3, and FSD1L. Analyses further revealed two genes associated with Crohn’s disease (CD), including novel associations at LRRC19 and SYNE4, and four genes associated with ulcerative colitis (UC), with NOMO2, BCAR3, and KLK2 representing new findings (Figure 2A-B). Compared to non-carriers with intermediate PRS (40-60%), rare variant carriers in the top PRS decile showed higher risks for IBD (HR 3.61, 95% CI 3.14-4.15), CD (HR 6.22, 95% CI 3.50-11.02) and UC (HR 3.34, 95% CI 1.89-5.90) (Figure 2C). Single-variant analysis revealed ten novel loci of common coding variants with five for IBD, one for CD, and four for UC (Figure 2D). Novel genes (SPON2 and LRRC19) show tissue- and cell-type-specific expression. Mendelian randomization suggested that genetically predicted expression or protein levels of the identified genes were associated with IBD. Druggability and mouse model data support their biological and therapeutic relevance. Conclusion Our study reveals novel IBD genes, demonstrates synergistic effects between rare variants and polygenic burden, which the value of integrating exome sequencing with PRS for risk prediction and precision medicine in IBD. Conflict of interest: Ruan, Xixian: I disclose no relevant conflict of interest. Sun, Yuhao: No conflict of interest Chen, Xuejie: No conflict of interest Wang, Xiaoyan: No conflict of interest Zhang, Zhenhua: No conflict of interest Shixian, Hu: No conflict of interest Li, Xue: No conflict of interest Dr. Chen, Jie: No conflict of interest