P1169 Multimorbidity and Disease Trajectories in Patients with INFLAMMATORY BOWEL DISEASES: Insights from Observational and Genetic Analyses

Abstract Background The multi-morbidity pattern of inflammatory bowel disease (IBD) remains under-explored. We integrated both observational and genetic data to elucidate multisystem comorbidities and health consequences of IBD. Methods Phenome-wide association study (PheWAS) based on the international classification of disease (ICD)-diagnosed IBD was conducted to explore its associations with 1,053 unique clinical outcomes in the UK Biobank. Disease trajectory analyses were implemented to illustrate sequential patterns of IBD-related comorbidities. The associations of genetic liability to IBD proxied by a polygenic score with identified clinical outcomes were examined to strengthen causality (N=385,917). To investigate potential shared genetic bases and causality, we performed a cross-trait linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomization (TSMR) analysis using the FinnGen biobank (N=377,277). The impact of IBD subtypes and the age at diagnosis were also evaluated in sensitivity analyses. Results A total of 5,782 cases with IBD (3,940 cases with UC and 1,800 cases with CD) were diagnosed at baseline in the UK Biobank. Observational PheWAS revealed elevated risks of all-cause mortality with HRs of 1.34 (95%CI=1.24-1.45, P<0.001), 1.61 (95%CI=1.41-1.83, P<0.001) and 1.22 (95%CI=1.10-1.34, P<0.001) for patients with IBD, CD or UC respectively. Increased mortality risk was noted across pediatric, early-onset, and later-onset IBD patients. Sequential patterns of IBD-related comorbidities were primarily found in cardiometabolic, respiratory, digestive and autoimmune diseases. The polygenic PheWAS, LDSC and TSMR analyses supported both strong genetic correlations and causal associations of IBD with immune-mediated (notably psoriatic arthropathies, psoriasis, dermatitis, asthma) as well as non-autoimmune diseases ( pneumonia, anemias, and renal failure). Conclusion Our observational and genetic analyses suggest multisystem comorbidities and consequences of IBD, highlighting the need for multidisciplinary clinical management and investigation of shared biologically or genetically regulated mechanisms in the pathogenesis of IBD.