Genetic and Transcriptomic Landscape of Colonic Diverticulosis

Overview

Journal Gut

Specialty Gastroenterology

Date 2024 Mar 5

PMID 38443061

Authors

Jungkyun Seo

Hongwei Liu

Kristin Young

Xinruo Zhang

Temitope O Keku

Corbin D Jones

Kari E North

Robert S Sandler

Anne F Peery

Affiliations

Soon will be listed here.

Abstract

Objective: Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case-control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders.

Design: We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders.

Results: We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including and , with potential causal effects on diverticulosis. Notably, upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis.

Conclusion: Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy.

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