Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
Schafmayer, C; Harrison, JW; Buch, S; et al.Lange, C; Reichert, MC; Hofer, P; Cossais, F; Kupcinskas, J; von Schönfels, W; Schniewind, B; Kruis, W; Tepel, J; Zobel, M; Rosendahl, J; Jacobi, T; Walther-Berends, A; Schroeder, M; Vogel, I; Sergeev, P; Boedeker, H; Hinrichsen, H; Volk, A; Erk, J-U; Burmeister, G; Hendricks, A; Hinz, S; Wolff, S; Böttner, M; Wood, AR; Tyrrell, J; Beaumont, RN; Langheinrich, M; Kucharzik, T; Brezina, S; Huber-Schönauer, U; Pietsch, L; Noack, LS; Brosch, M; Herrmann, A; Thangapandi, RV; Schimming, HW; Zeissig, S; Palm, S; Focke, G; Andreasson, A; Schmidt, PT; Weitz, J; Krawczak, M; Völzke, H; Leeb, G; Michl, P; Lieb, W; Grützmann, R; Franke, A; Lammert, F; Becker, T; Kupcinskas, L; D'Amato, M; Wedel, T; Datz, C; Gsur, A; Weedon, MN; Hampe, J
Date: 19 January 2019
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: ...
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
Institute of Biomedical & Clinical Science
College of Medicine and Health
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