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Diverticular Disease GWAS Leads to Dozens of New Risk Loci

NEW YORK (GenomeWeb) – Using genome-wide association and phenome-wide association approaches, a team led by researchers at the University of Michigan has started teasing out the genetics and biology of diverticular disease — a common condition characterized by painful pockets or pouches that form from the large intestine.

These outcroppings, which can become infected or inflamed, can stem from the more modest gastrointestinal tract outcroppings that occur during diverticulosis.

"Progression from diverticulosis to diverticular disease is poorly understood," first and corresponding author Lillias Maguire, a researcher in the department of surgery at the University of Michigan, and her colleagues wrote, noting that in the past, "only one genome-wide association study has been performed, to our knowledge, in which three loci have been identified."

As they reported online yesterday in Nature Genetics, the researchers first performed a GWAS involving nearly 410,000 individuals with or without diverticular disease to find all three known loci and 39 loci not previously linked to the gastrointestinal disease — associations they verified with data for another 2,572 cases and 28,649 controls. Their subsequent phenome-wide association analysis pointed to shared etiology with other traits, including obesity and hernia risk.

"Genes in these associated loci have roles in immunity, extracellular matrix biology, cell adhesion, membrane transport, and intestinal motility," the authors reported.

The team first compared genotyping profiles at around 30 million variants across the genome in 27,444 UK Biobank participants with diverticular disease and 382,284 without, uncovering 154 suspicious SNPs. These variants occurred at 40 genome-wide significant loci, they reported, along with 112 more suggestive loci.

Through testing in a validation cohort that included 2,572 cases and 28,649 controls enrolled through the Michigan Genomics Initiative, the team confirmed all 40 associations as well as diverticular disease associations at two of the suggestive sites in the genome.

The researchers took all 42 loci forward for their subsequent gene and pathway prioritization, expression quantitative trait locus, and PheWAS analyses, which hinged on pathway and expression data, insights from the Genotype-Tissue Expression (GTEx) consortium, and nearly 800 traits assessed for the UK Biobank project, respectively.

In addition to finding enhanced expression for genes in and around the diverticular disease-linked loci in mesenchymal stem cells and at least four connective tissue cell types, they noted that the associated genes appeared to be co-expressed with genes or pathways implicated in mesenchymal, vascular, and connective tissue functions.

Also, more than a dozen diverticular disease-associated variants overlapped with eQTLs in the sigmoid or transverse colon, the team reported. On the PheWAS front, meanwhile, association data for 780 UK Biobank traits implicated almost two dozen of the diverticular disease-associated loci in additional traits, ranging from hematological traits or hernia to connective tissue and vascular biology traits.

The study "provides a framework for future functional studies," the authors concluded, "and identifies possible targets for therapeutic development."