Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease

Abstract

Diverticular disease is common and has a high morbidity. Treatments are limited owing to the poor understanding of its pathophysiology. Here, to elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) from the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease; 39 of these loci are novel. Using data-driven expression-prioritized integration for complex traits (DEPICT), we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that have a role in vascular and mesenchymal biology. Genes in these associated loci have roles in immunity, extracellular matrix biology, cell adhesion, membrane transport and intestinal motility. Phenome-wide association analysis of the 42 variants shows a common etiology of diverticular disease with obesity and hernia. These analyses shed light on the genomic landscape of diverticular disease.

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

“…Additional replication was observed for further eight loci in a combined meta-analysis of European colonoscopy cohorts with a European population cohort from Michigan (tables 2 and 3). Thirty-six out of 48 identified risk loci have been previously reported15 with genome-wide significant association (tables 2 and 3 and online supplementary table 4). All previously replicated risk loci for diverticular disease ( ARHGAP15 , FAM155A , COLQ) and ( GPR158, ABO, ANO1/FADD, ELN, BMPR1B, SLC35F3, SEM1/SHFM1 ) were identified both in the current GWAS and replication analyses with similar ORs to those reported by Sigurdsson et al 14 and Maguire et al 15 (table 3).…”

“…Overlap of risk loci to a previous GWAS by Maguire et al 15 and Sigurdsson et al 14 with the corresponding risk locus is indicated. Current GWAS risk loci are numbered descending by the p value in the discovery analysis.…”

“…For replication a nominal significance level of p<0.05 and consistency in OR direction between the discovery and replication stage was applied. Additional replication was achieved by including replication data presented by Maguire et al 15 (online supplementary table 4) from European samples (n=29 367) from the Michigan genome initiative into a combined meta-analysis of all European replication cohorts (n=36 089 samples). Details on the genotyping, quality control and meta-analysis are provided in the online supplementary materials and methods section.…”

“…The column ‘loci overlap’ indicates an overlap of the respective risk loci to a risk locus recently identified in a GWAS by Maguire et al 15. The corresponding risk locus number is given as ( Mag .#1–82), with bold print indicating prior attainment of genome-wide significance.…”

“…A previous genome-wide association study (GWAS) from Iceland identified associations of variants in ARHGAP15 and COLQ with uncomplicated diverticular disease and variants in FAM155A with diverticulitis 14. Additionally, 37 susceptibility loci with genome-wide significance were identified in a recent study from Maguire et al ,15 with replication of 8 loci.…”