RF3 - Genome-Wide Association Study Highlights Shared Inherent Risk for Diverticular Disease and Aortic Aneurysm

Saturday, June 1, 2024

3:17 PM – 3:21 PM ET, USA

Location: Room 314-317

Senior Author(s)

LM

Lillias Maguire, MD FACS

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

Disclosure information not submitted.

Abstract Podium Presenter(s)

Kerri Lopez, MD (she/her/hers)

Colon & Rectal Surgery Fellow
University of Pennsylvania
University of Pennsylvania
Philadelphia, PA, United States

All relevant financial disclosures have been managed and will be listed below.
This individual has no financial relationships with ineligible companies.

Author(s)

AK

Alyson H. Kim, BA

Medical Student
Drexel University College of Medicine
Philadelphia, Pennsylvania, United States

Disclosure information not submitted.
SD

Scott Damrauer, MD

Associate Professor of Surgery and of Genetics
Perelman School of Medicine
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, PA, United States

Disclosure information not submitted.
Christopher J. Neylan, MD

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

All relevant financial disclosures have been managed and will be listed below.
This individual has no financial relationships with ineligible companies.

Purpose/Background: Diverticular disease (DD) is clinically associated with connective tissue disorders including aortic aneurysm, suggesting potential underlying shared biology. We propose to investigate shared genetic risk factors for aneurysmal disease and DD using a large, diverse genome-wide association study.

Methods/Interventions: We performed a diverse multi-population genome-wide association study (GWAS) of diverticular disease in the United Kingdom BioBank and VA Million Veteran Program comprising 114,806 participants with and 934,030 without DD. Downstream analyses included interrogating the association of significant DNA variants with other health and disease traits using the OpenGWAS platform comprising 46,103 datasets, identifying potential causal genes by the presence of coding variants and variants that affect protein expression, and tissue- and gene-set enrichment analysis.

Results/Outcomes: We identified 2,273 variants at 284 loci associated with DD at genome-wide significance (p < 5e-8), including the PRKG1, ELN, and SMAD3 loci, all known to cause familial thoracic aortic aneurysms and dissections. Notably, we identified missense coding variants in ELN that associated with DD. Additionally, variants at 13 DD risk loci associated with multiple measures of aortic size and distensibility. 3,021 DNA variants associating with DD were significantly (p < 5e-8, FDR <=0.01) associated with the expression of 247 genes in both the sigmoid colon and aorta. Gene-set analyses found significant (false discovery rate (FDR) < 0.01) enrichment of DD gene expression in arterial and aortic valve tissue and identified 36 vascular pathways significantly (FDR < 0.01) enriched for DD genes.

Conclusion/Discussion: In this large GWAS of DD in a diverse population, we identify multiple compelling genetic links between DD and aortic aneurysmal disease. These data suggest that clinical associations between DD and aneurysm may be due to shared genetic, rather than environmental, risks and present multiple compelling opportunities for further research.