Diverticular disease genome-wide association meta-analysis identifies 257 novel loci, implicates structure and motility

Abstract

Background and aimsDiverticular disease is a common and morbid complex phenotype influenced by both genetic and environmental risk factors. The aim of the current study is to elucidate the genetic architecture of diverticular disease and to corroborate those results with tissue-based analysis. MethodsWe performed the largest genome-wide association study (GWAS) meta-analysis for diverticular disease. We employed multiple downstream analytic strategies, including tissue and pathway enrichment, statistical fine-mapping, protein quantitative trait loci, drug-target investigations, and linkage disequilibrium score regression to prioritize causal genes. We utilized single-cell RNA sequencing data and quantitative analysis of surgically resected colon specimens to corroborate our computational biology results. ResultsOur GWAS meta-analysis included 1.3 million individuals across three cohorts and identified 565 independent signals (257 novel) associated with diverticular disease. These were mapped to 432 unique genes. Several lines of evidence linked these genes to alterations in connective tissue biology and colonic motility. Analysis of single-cell RNA sequencing data revealed that prioritized diverticular disease-associated genes are enriched for expression in colonic smooth muscle, fibroblasts, and interstitial cells of Cajal. Quantitative analysis of surgically resected colon specimens found a substantial (43%) reduction in the density of elastin present in the sigmoid colon among those with severe diverticulitis relative to those with diverticulosis. ConclusionDiverticular disease is predominantly a disorder of connective tissue biology and colonic motility. Specifically, decreased density of elastin in the muscularis propria may predispose not to diverticulosis but to diverticulitis itself.