Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis

Abstract

Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10−18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10−10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10−11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study.

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

“…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). The most significant novel risk variant rs9960286 is located near CTAGE1 (cutaneous T-cell lymphoma-associated antigen 1) with a p value of 2.3×10 −10 and 0.002 (OR allelic =1.14 (95% CI 1.05 to 1.24)) in the replication analysis.…”

“…Among these loci, 12 are novel risk loci for diverticular disease and 5 of the novel loci were also replicated in a European clinical cohort with detailed phenotyping and colonoscopy data for all controls. The three previously known risk loci14 ARHGAP15 , COLQ and FAM155A are among the validated loci and support the robustness of the phenotype and analysis on both the previous study and our analysis. A recent study by Maguire et al 15, who analysed a smaller UK Biobank dataset (n=409 728 individuals) compared with the current study (n=451 099) identified 40 loci with genome-wide significance using GWAS results publicly available from the Roslin Gene Atlas.…”

“…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.…”

“…Epidemiological12 and twin studies13 have estimated the heritability of diverticular disease at 40%–53%. 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.…”

Multi-ancestry Genome- and Phenome-wide Association Studies of Diverticular Disease in Electronic Health Records with Natural Language Processing enriched phenotype algorithm

“…Twin studies reveal that genetic heritability of diverticular disease is estimated to be up to 53% (95% Confidence Interval (CI), 45-61%) 6 . To date, three GWAS have identified 52 genetic susceptibility loci associated with diverticular disease [23][24][25] .…”