OP20 Expanding the genetic spectrum of inflammatory bowel disease through large-scale exome sequencing

Abstract Background Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is highly heritable, with more than 50% of the variation in disease risk explained by genetics 1. Genome-wide association studies (GWASs) have identified over 300 IBD-associated loci 2, primarily underpinned by non-coding variants. Initial sequencing efforts have identified rare coding variants associated with CD 3, offering novel insights into disease mechanisms. However, the impact of low-frequency and rare coding variants in IBD remains underexplored. Methods We conducted single variant and meta-analysis across six different whole-exome/genome sequencing datasets. After quality control, 167,172 non-synonymous variants with minor allele frequency (MAF) between 0.0001 and 0.1 in gnomAD v4.1 (Non-Finnish European, NFE) were tested for association across 86,213 IBD cases (44,131 CD, 32,748 UC, and 9,334 IBD-uncertain) and 478,363 controls. Variants with P < 3×10-7 were considered significant. Additionally, very rare (MAF < 0.001) non-synonymous (NSYN) and protein-truncating variants (PTVs) were analysed for gene-level burden differences in each dataset and meta-analysed, with P < 2.5×10⁻⁶ as the threshold for significance. Results In the single variant analysis, we found 55 CD, 17 UC, and 20 IBD associated variants. After checking their linkage disequilibrium (LD) with known signals, 27 (CD), 14 (UC), and 19 (IBD) novel associations were defined (Figure 1). For example, a frameshift variant in TNFRSF6B (E45fs, MAF = 0.00055), missense variants in FAM120B (S431P, MAF = 0.0018) and IFNL2 (H32R, MAF = 0.0045) were significantly associated with CD, UC and IBD, respectively. Our results expand the list of TNF receptors involved in IBD susceptibility, and provide additional support to the role of IFNλ signalling on IBD pathogenesis. The burden test identified 18 genes (Figure 2) with a significantly different burden of very rare NSYNs or PTVs in CD (N = 9), UC (N = 4), or IBD (N = 12) cases versus controls. Among them, NOD2, ATG4C, ADCY7, and ITGAV had orthogonal support from GWASs, either from independent common coding variants or non-coding variants driving gene-expression differences, suggesting the joint contribution of common and rare-coding variants in these genes to IBD susceptibility. In addition, IBD patients showed an increased burden of very rare variants in IL10RA, a known monogenic IBD gene, expanding the phenotypic spectrum to include a more complex form of IBD. Conclusion In conclusion, we report novel rare variants and genes associated with IBD based on the meta-analysis of 86,213 IBD cases and 478,363 controls. This study provides novel insights into the biology of IBD and may prompt further investigation into new therapeutics. References 1. Chen GB, Lee SH, Brion MJ, et al. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data. Hum Mol Genet. Sep 1 2014;23(17):4710-20. doi:10.1093/hmg/ddu174 2. Liu Z, Liu R, Gao H, et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet. May 2023;55(5):796-806. doi:10.1038/s41588-023-01384-0 3. Sazonovs A, Stevens CR, Venkataraman GR, et al. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nat Genet. Sep 2022;54(9):1275-1283. doi:10.1038/s41588-022-01156-2