P1196 Genomic structural variation and polygenic risk score for Inflammatory Bowel Disease

Abstract

Abstract Background Genome-wide association studies (GWAS) of patients with inflammatory bowel disease (IBD) have identified multiple single-nucleotide polymorphisms (SNPs) and genetic variants involving structural changes in the DNA sequence. SNPs and structural variants (SVs) can play a crucial role in IBD pathogenesis. In this study, we evaluated large deletions induced by SVs in patients with IBD. Additionally, we evaluated the ethnic contribution to a polygenic risk score (PRS) for IBD. Methods Seventy-five Patients with IBD of Korean ancestry from Seoul National University Bundang Hospital (SNUBH) were subjected to whole-genome sequencing (49 patients with UC and 26 patients with CD). SVs involving large deletions were detected and analyzed by using the Genome Aggregation Database (gnomAD) and AnnotSV. The SVs were prioritized based on a list of 241 IBD-associated SNPs identified in the previous GWAS. The prediction performance of European- and Korean-derived PRSs for IBD was also evaluated. For calculating PRS, we applied previously published models derived from the European and Korean populations, respectively, and used Korean Genome and Epidemiology Study (KoGES) database as the Korean controls. Results We found a total of 146 SVs involving large deletions in the IBD cohort. Among them, 10 SVs were annotated as likely pathogenic, according to AnnotSV and American College of Medical Genetics and Genomics guidelines; 24 SVs had the probability of being loss-of-function intolerant (pLI ≥ 0.9). We found that the frequency of large deletions that overlapped with the regions coding NOTCH1, HGF, PTPN2, and SENP7 were rare in the IBD cohort compared to the gnomAD population (Table). The large deletions that overlapped with the regions coding IL2RA, ITGA4, BANK1, and STAT3 were identified in the IBD cohort but not in the gnomAD population. The PRS for IBD in the IBD cohort was significantly higher than that in the Korean controls under the Korean- or European-derived model (Figure A). However, the PRSs for CD or UC were not able to distinguish patients with CD and UC in the IBD cohort (Figure B and C). Conclusion Our finding suggests that SVs involving large deletion may be an important genomic variability in predicting the development of IBD. The PRS for IBD can predict IBD development without ethnic specificity.