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.
- diverticular disease
- intestinal motility
- genetic polymorphisms
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CS, JWH and SB contributed equally.
TW, CD, AG, MNW and JH contributed equally.
Contributors JWH, SB, CL, FC: performed the experiments, analysed the data and wrote the manuscript; JWH, AH, SB, AR, WR, NB: performed the bioinformatic analyses; CL, FC, MB: performed real-time PCR, histological, immunohistochemical analyses; CS, FL, LK, MZ, WvS, MCR, JR, TB coordinated, managed collection of samples, performed phenotyping; WL coordinated and supervised collection of samples; SN, UH-S, FR, PH, BS, WK, JT, MZ, JR, AW-B, TJ, JK, MS, IV, PS, HB, HH, AV, J-UE, GB, AH, S H, SW, ML, TK, SB, UH-S, LP, LSN, H-WS, SZ, SP, GF, AA, PTS, GL, JW, FL, TB, LK, PM, RG, VM: obtained the samples, performed phenotyping, interpretation of data; MK, MD’A, SZ, AF, MB, HV, WK, FL, RVT, JT gave conceptual advice, participated in the discussions, interpretation of the results, editing of the manuscript; CS, JH, MW, CD, AG, TW: conceived the experimental and analytical design, analysed data, wrote and reviewed the manuscript. All authors critically revised and contributed to the final manuscript.
Funding The work presented in this manuscript was supported by the German Research Council (DFG, Ha3091/9-1, WE2366/5-1) and the Austrian Science Fund (FWF, I1542-B13). Further support was received from SPAR Austria and from institutional funds from the Christian-Albrechts-University Kiel. The recruitment of the West German cohort was supported by a grant from the Faculty of Medicine, Saarland University (HOMFOR grant T201000747) to MCR. This study was supported by a grant of the Research Council of Lithuania No. SEN-06/2015/PRM15-135. AA, PTS were supported by the Stockholm County Council (ALF project). MD’A was supported by the Swedish Research Council (VR grant 2017-02403). Data access to the UK Biobank data was granted under project numbers 22691 and 9055.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.
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