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

Additive effect between a rare pathogenic variant in a heritable thoracic aortic disease gene and a polygenic risk score derived from aortic diameter

This genetic association study used two electronic health record-linked biobanks, the Penn Medicine Biobank and MyCode. Between 0.2% and 0.3% of participants carried a pathogenic or likely pathogenic variant in one of the eleven genes with strong or definitive evidence for heritable thoracic aortic disease, with an odds ratio of 13.5 (95% CI 5.3-34.6) for aneurysm or dissection. A polygenic risk score derived from a genome-wide association study of aortic diameter was associated with an odds ratio of 1.43 per standard deviation (95% CI 1.39-1.47). Among carriers, disease prevalence was 2.32-fold higher in the top polygenic quintile than in the bottom quintile (95% CI 1.29-4.17).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value of this work is that it quantifies, within the same carrier, what polygenic background adds to the rare variant: a 2.3-fold difference between extreme quintiles is not trivial when discussing thresholds for prophylactic surgery. The weakness lies in the outcome, derived algorithmically from health records, and in a carrier count that remains modest despite two biobanks. For now this is a solid research argument, not yet a stratification tool to use in clinic.

Analysis by Dr Thibaut Benquey