Thoracic aortic disease: prognostic role of gene variants and polygenic risk scores.

Authors

John DePaolo, Diane T Smelser, Dongchuan Guo, Sarah Abramowitz, Gina Sisti, Renae Judy, Nimesh D Desai, Wilson Y Szeto, Michael G Levin, Hannah Mirshahi, Gregory Salzler, Evan Ryer, James R Elmore, Scott A LeMaire, David J Carey, Dianna M Milewicz, Scott M Damrauer

Published in

European heart journal. Sep 01, 2026. Epub Sep 01, 2026.

Abstract

Thoracic aortic aneurysm and dissection (TAAD) can have catastrophic health consequences. Eleven genes have strong or definitive evidence for causing heritable TAAD (HTAAD). The aim of this work was to determine the prevalence and effect of rare, pathogenic or likely pathogenic (P/LP) variants in HTAAD genes on the association of TAAD diagnoses, and whether increased polygenic risk is associated with an additive effect on monogenic risk.
This genetic association study used data from Penn Medicine Biobank (PMBB) and MyCode Biobank. P/LP HTAAD gene variants were adjudicated according to American College of Medical Genetics and Genomics standards. A polygenic risk score (PRS) was derived from a genome-wide association study of aortic diameter to assess polygenic TAAD risk. The main outcome of interest, TAAD, was identified using an algorithmic review of electronic health records. Regression analyses were performed to determine the monogenic and polygenic effects on TAAD risk.
Across the two cohorts, .2%-.3% of participants carried a P/LP HTAAD gene variant. Individuals carrying P/LP HTAAD gene variants had a significantly higher odds of TAAD compared to non-carriers [odds ratio (OR) 13.5, 95% confidence interval (CI) 5.3-34.6, P < .001] with variable effects when stratified by gene. A one standard deviation increase in the PRS was associated with an OR for TAAD of 1.43 (95% CI 1.39-1.47, P < .001). TAAD prevalence was higher among individuals carrying a P/LP HTAAD gene variant in the highest PRS quintile compared to carriers in the lowest PRS quintile (relative risk 2.32, 95% CI 1.29-4.17, P < .01), suggesting that polygenic risk may be an important additive factor in rare variant TAAD risk.
P/LP HTAAD gene variants confer a substantial population-level increased risk of TAAD. Polygenic risk represents an additive factor for rare variant TAAD risk, suggesting that integrating monogenic and polygenic risks has the potential to enhance patient risk stratification and treatment.

PMID:
42678067
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.

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