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Voskuil, M D; Spekhorst, L M; van der Sloot, K W J; Jansen, B H; Dijkstra, G; van der Woude, C J; Hoentjen, F; Pierik, M J; van der Meulen, A E; de Boer, N K H; Löwenberg, M; Oldenburg, B; Festen, E A M; Weersma, R K
Journal of Crohn's and colitis, 06/2021, Volume: 15, Issue: 6Journal Article
Abstract Background and Aims Inflammatory bowel disease IBD phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores GRS to disentangle the genetic contributions to IBD phenotypes. Methods Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts cohort A, n = 1097; cohort B, n = 2156. Genetic risk scoring GRS was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS–phenotype (false-discovery rate FDR corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B. Results Crohn’s disease CD GRS were associated with fibrostenotic CD R2 = 7.4%, FDR = 0.02 and ileocaecal resection R2 = 4.1%, FDR = 1.6E-03, and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis UC GRS R2 = 7.1%, FDR = 0.02 and primary sclerosing cholangitis PSC GRS R2 = 3.6%, FDR = 0.03 were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour R2 = 1.7%, FDR = 0.04. Conclusions Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.
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