Genome-First Approach to Rare and Common Variant Risk of Thoracic Aortic Aneurysm and Dissection

Thoracic aortic aneurysm and dissection (TAAD) can have catastrophic health consequences. Eleven genes have strong or definitive evidence for causing heritable TAAD (HTAAD). However, patients are seldom tested for rare pathogenic (P) or likely pathogenic (LP) variants in these HTAAD genes absent a strong family history or syndromic features, and little is known about either their prevalence in the general population or the associated TAAD risk. Furthermore, the degree to which common genetic variation associated with TAAD modifies rare variant pathogenicity is unknown.

Penn Medicine Biobank (PMBB) and MyCode participants volunteered to have electronic health records linked to biospecimen data including DNA which has undergone genome-wide genotyping and whole exome sequencing. P/LP HTAAD gene variants were adjudicated according to American College of Medical Genetics and Genomics standards, and logistic regression was performed to determine the associated risk of prevalent TAAD. An ascending aortic diameter (AscAoD) polygenic risk score (PRS) was derived from a genome-wide association study (GWAS) of aortic diameter to assess common variant TAAD risk, and regression analyses were performed to determine the modifying effect this PRS had on penetrance of rare variants.

Across the two analytic cohorts, 0.2-0.3% of participants carried a P/LP HTAAD gene variant. Compared to individuals without a P/LP variant, carrying a P/LP HTAAD variant was associated with a 13.5-fold increased risk of a diagnosis of TAAD (95% confidence interval [CI] 5.3 to 34.6, P<0.001) with variable effects when stratified by gene. A one standard deviation increase in the AscAoD PRS was associated with a 1.43-fold increased risk of TAAD (95% CI 1.39 to 1.47, P<0.001). 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 to 4.17, P<0.01) suggesting that common variant risk may be an important modifier of rare variant risk for TAAD.

Our results indicate that P/LP HTAAD gene variants confer a significant increased risk of TAAD in the population at-large, and that polygenic risk may be an important modifier of rare variant risk.