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.

Figure 1:

Study Design. Graphic representation of study design. GWAS: Genome-wide association study. SNPs: single nucleotide polymorphisms. PheWAS: Phenome-wide association study. GTEx: Genotype-Tissue Expression project. DEPICT: Data-driven Expression-Prioritized Integration for Complex Traits. eQTL: Expression Quantitative Trait Loci

Figure 2A/B:

Tissue and cell type enrichment analysis. Plots showing the enrichment of loci associated with diverticular disease (p < 1 × 10−5 in the UKBB; N=27,444 cases/382,284 controls) in specific cell types (A) and tissues (B). Enrichments are grouped according to system or cell type and significance; annotations above the dashed line have FDR ≤ 0.20. Data corrected for multiple comparisons using Benjamini-Hochberg method. Top tissue in each category labelled.

Figure 3:

Phenome-wide association matrix. Filtered association matrix highlighting vascular, gastrointestinal, connective tissue, hematologic, morphometric, and dietary traits associated with loci of interest in the UKBB (27,444 cases/382,284 controls) Data controlled for multiple comparisons using Benjamini-Hochberg method, filtered at FDR<5%, and clustered at h=0.2.

Figure 4:

Plausible biological pathways underlying risk loci associated with diverticular disease. Bold gene symbols indicate replication in MGI. * indicates prior identification in GWAS