Abstract
Diverticular disease is a common and morbid complex phenotype influenced by both innate and environmental risk factors. We performed the largest genome-wide association study meta-analysis for diverticular disease, identifying 126 novel loci. Employing multiple downstream analytic strategies, including tissue and pathway enrichment, statistical fine-mapping, allele-specific expression, protein quantitative trait loci and drug-target investigations, and linkage disequilibrium score regression, we prioritized causal genes and produced several lines of evidence linking diverticular disease to connective tissue biology and colonic motility. We substantiated these findings by integrating single-cell RNA sequencing data, showing that prioritized diverticular disease-associated genes are enriched for expression in colonic smooth muscle, fibroblasts, and interstitial cells of Cajal. In quantitative analysis of surgical specimens, we found a substantial reduction in the density of elastin present in the sigmoid colon in severe diverticulitis.