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

Abstract

ObjectiveDiverticular 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.DesignDiscovery 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.ResultsWe 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 CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn 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.

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

“…The GWAS of diverticular disease in the MA population identified one genome-wide significant locus (Figure 2) at 2q22.3 within the ARHGAP15 gene, which encodes Rho GTPase activating protein 15, and has been consistently reported in previous GWAS of diverticular disease [23][24][25] . The association patterns between two conditions are largely similar; the diverticulitis GWAS showing more significant and larger ORs compared to the diverticulosis GWAS's in general ( Table 3).…”

“…To date, patient identification in previous GWAS studies were partially limited in that they mostly used inpatient medical coding which might resulted in under-diagnosis of the case patients as imaging reports were not used, and/or misclassification of controls who possibly have diverticular disease. In the most recent GWAS of diverticular disease 24 , the replication cohorts were manually reviewed with human hands-on input from physicians/technicians; however, manual review has a limited application to larger population-based datasets in its lack of scalability. Our phenotyping approach showed a significant improvement in performance (algorithm PPVs ≥ 0.94, 3.5 fold increase in diverticulosis patient identification) compared with use of only ICD-codes in patient classification, (Table 2) and supports the importance of leveraging the full breadth of data captured in EHRs 42,43 .…”

“…To evaluate, we compared our NLP-enriched phenotype algorithm results against the results of an ICD-based phenotyping method that has been commonly implemented in previous GWASs of diverticular disease [23][24][25] . Using the phecode map v1.2 37 for diverticular disease (ICD-9 562), we excluded patients with any related gastrointestinal manifestations such as 'ulcerative enterocolitis' (ICD-9 556), 'regional enteritis' (ICD-9 558), 'volvulus of intestine' (ICD-9 560.2), etc.…”

“…We also conducted PheWAS of the 52 reported GWAS susceptibility loci from the three existing GWASs of diverticular disease [23][24][25] . The genomic position of the 52 loci were converted to GrCh37/hg19 (40 loci from Maguire et al 23 Table 5).…”

“…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] .…”