Gut, May 2019, Vol.68(5), pp.854-865
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. 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. 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 with a p value of 2.3×10 and 0.002 (OR=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, (OR 1.32, 95% CI 1.12 to 1.56), (OR 1.21, 95% CI 1.04 to 1.42), (OR 1.17, 95% CI 1.03 to 1.33) and (OR 1.17, 95% CI 1.03 to 1.33). 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 ; Genetic Polymorphisms ; Intestinal Motility ; Genome-Wide Association Study ; Colonic Diseases -- Genetics ; Connective Tissue -- Physiology ; Diverticular Diseases -- Genetics ; Epithelium -- Physiology ; Neuromuscular Junction -- Physiology
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