EP979 - The Genetic Architecture of Diverticular Disease

Sunday, May 11, 2025

2:25 PM – 3:10 PM PT

Location: Monitor 4, Sails Pavilion, Upper Level

Presenting Author(s)

Christopher J. Neylan, MD

General Surgery Resident
Hospital of the University of Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no financial relationships with ineligible companies.

Author(s)

KH

Katherine Hartmann, MD, PhD

Resident, Radiology
University of Pennsylvania
Philadelphia, Pennsylvania, United States

Disclosure information not submitted.
SA

Sarah Abramowitz, n/a

Medical Student/Sarnoff Fellow
University of Pennsylvania Perelman School of Medicine
Philadelphia, Pennsylvania, United States

Disclosure information not submitted.
ML

Michael Levin, MD

Assistant Professor of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania, United States

Disclosure information not submitted.
Jeffrey L. Roberson, MD

Resident
The Hospital of the University of Pennsylvania
The Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no financial relationships with ineligible companies.
SD

Scott Damrauer, MD

Associate Professor of Surgery
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States

Disclosure information not submitted.

Senior Author(s)

LM

Lillias Maguire, MD (she/her/hers)

Assistant Professor of Surgery
University of Pennsylvania
Philadelphia, Pennsylvania, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no relevant relationships with ineligible companies.

All of the relevant financial relationships listed below have been mitigated.

Christopher J. Neylan, MD: This individual has no financial relationships with ineligible companies.

Jeffrey L. Roberson, MD: This individual has no financial relationships with ineligible companies.

Lillias Maguire, MD: This individual has no relevant relationships with ineligible companies.

Image or Table (Do Not add text here):

Purpose/Background: Diverticular disease is estimated to be 40-53% heritable. A small number of genome-wide association studies (GWASs) have identified genetic variants associated with diverticular disease, and several papers subsequently published polygenic risk scores to predict the risk of diverticulitis. However, little is known about the biological function of the underlying genetic variants.

Methods/Interventions: Based on a GWAS meta-analysis of diverticular disease, we defined genetic loci (r2 threshold 0.01, 500kb window), used CARMA to perform statistical fine-mapping within those loci, and created LocusZoom plots to define one or multiple independently significant signals per locus. We then prioritized one gene per signal based on HyPrColoc, MAGMA, and OpenTargets annotations. Finally, we analyzed the biological function of the prioritized genes through multiple pathways including EnrichR analysis, allele specific expression (ASE), and a phenome-wide association study (PheWAS) in the Penn Medicine Biobank.

Results/Outcomes: The GWAS meta-analysis included 114,806 participants with diverticular disease and 819,224 without in the Million Veterans Program and United Kingdom Biobank cohorts. We defined 236 loci and fine-mapped an additional 86 independently significant secondary variants. Gene prioritization yielded a list of 229 unique genes, including LTBP4 and ELN. EnrichR analysis revealed increased expression in the sigmoid colon and extracellular matrix, and at least one gene demonstrated clear evidence of allele specific expression. Finally, a PheWAS revealed strong association with diverticulitis and with other connective tissue disorders (e.g. hernia).

Conclusion/Discussion: This analysis provides biological insight into the genetic contribution to diverticular disease, specifically suggesting connective tissue biology and implicating several specific genes.