Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer C, Harrison JW, Buch S, 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 JU, 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 (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 68

Pages Range: 854-865

Journal Issue: 5

DOI: 10.1136/gutjnl-2018-317619

Abstract

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.

Authors with CRIS profile

Involved external institutions

Technische Universität Dresden Germany (DE) Elblandkliniken Germany (DE) Karolinska Institute Sweden (SE) Christian-Albrechts-Universität zu Kiel Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Städtisches Krankenhaus Kiel Germany (DE) University of Exeter United Kingdom (GB) Klinikum Osnabrück Germany (DE) Universitätsklinikum Halle (Saale) Germany (DE) Paracelsus Medizinische Privatuniversität Austria (AT) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Universitätsklinikum des Saarlandes (UKS) Germany (DE) KRAGES Burgenländische Krankenanstalten-Ges.m.b.H. Austria (AT) Städtisches Klinikum Lüneburg Germany (DE) Lithuanian University of Health Sciences / Lietuvos sveikatos mokslų universitetas (LSMU) Lithuania (LT) Evangelisches Krankenhaus Kalk Germany (DE) Krankenhaus Dresden-Friedrichstadt, Städtisches Klinikum Germany (DE) Medizinische Universität Wien Austria (AT) HELIOS Kliniken Germany (DE) Kreiskrankenhaus Freiberg gGmbH Germany (DE)

How to cite

APA:

Schafmayer, C., Harrison, J.W., Buch, S., Lange, C., Reichert, M.C., Hofer, P.,... Hampe, J. (2019). Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. Gut, 68(5), 854-865. https://doi.org/10.1136/gutjnl-2018-317619

MLA:

Schafmayer, Clemens, et al. "Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms." Gut 68.5 (2019): 854-865.

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