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Colon
Original research
Genetic and transcriptomic landscape of colonic diverticulosis
  1. Jungkyun Seo1,
  2. Hongwei Liu2,
  3. Kristin Young1,
  4. Xinruo Zhang1,
  5. Temitope O Keku3,
  6. Corbin D Jones4,
  7. Kari E North1,
  8. Robert S Sandler5,
  9. Anne F Peery3
  1. 1 Department of Epidemiology, The University of North Carolina, Chapel Hill, North Carolina, USA
  2. 2 Department of Genetics, The University of North Carolina, Chapel Hill, North Carolina, USA
  3. 3 Center for Gastrointestinal Biology and Disease, The University of North Carolina, Chapel Hill, North Carolina, USA
  4. 4 Department of Biology and Integrative Program for Biological and Genome Sciences, The University of North Carolina, Chapel Hill, North Carolina, USA
  5. 5 Gastroenterology and Hepatology, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr Anne F Peery, Center for Gastrointestinal Biology and Disease, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; anne_peery{at}med.unc.edu

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 CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13, with potential causal effects on diverticulosis. Notably, ENTPD7 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.

  • DIVERTICULAR DISEASE
  • GENE EXPRESSION
  • GENE REGULATION

Data availability statement

Data are available in a public, open access repository (dbGap assession number phs003556.v1.p1).

https://doi.org/10.1136/gutjnl-2023-331267

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    Data availability statement

    Data are available in a public, open access repository (dbGap assession number phs003556.v1.p1).

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    Footnotes

    • Contributors The study was designed and conceived by JS, CDJ, KN, RSS and AFP, with input from HL, KY, XZ and TOK. All formal analyses were performed by JS. RNA-seq data processing was done by HL in close consultation with CDJ. The manuscript was drafted by JS, CDJ, KN and AFP and edited with input from all authors. AFP is the guarantor. All authors reviewed and contributed to the discussion of findings and the crafting of the manuscript.

    • Funding The project described was supported by the National Institutes of Health, through Grant Award Numbers NIH R01DK094738 (RSS), R01DK132050 (AFP), P30 DK034987 (RSS) and T32HL129982 (contact PI: KN) for JS. The project was also supported in part by the University Cancer Research Fund to Lineberger Comprehensive Cancer Center.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.