Performance of Cardiovascular Polygenic Risk Scores in Carotid Stenosis Identification

Background: Clinically significant carotid stenosis remains a major cause of ischemic stroke (IS), yet prediction of disease progression is limited. Polygenic risk scores (PRSs) for coronary artery disease (CAD) and peripheral artery disease (PAD) have demonstrated associations with atherosclerosis burden and major cardiovascular disease (CVD) events, but whether these insights extend to carotid stenosis is unclear. We evaluated the association and discriminative performance of validated PRSs for CAD, PAD, IS, and carotid intima-media thickness (cIMT) with carotid stenosis. Methods: Carotid stenosis was identified in genotyped Mass General Brigham Biobank participants using validated ICD- and CPT-based phenotyping algorithms. Logistic regression adjusted for age, sex, and 10 ancestry principal components assessed PRS associations. Incremental discrimination was evaluated using changes in Harrell's C-statistic. Results: Compared with 52,636 controls, 670 participants with carotid stenosis were more frequently male (61.5% vs 44.1%), older (70.8 SD 9.0 vs 53.4 SD 17.2 years), and more likely to be European (95.7% vs 84.1%). The IS (OR 1.31, 95% CI 1.21?1.41), CAD (OR 1.62, 95% CI 1.50?1.75), and PAD (OR 1.66, 95% CI 1.54?1.80) PRSs were each associated with carotid stenosis (all p<0.0001), while the cIMT PRS was not (p=0.28). The PAD PRS demonstrated the greatest improvement in discrimination beyond age, sex, and ancestry (?C-statistic 0.017; C-statistic 0.845, 95% CI 0.833?0.856). A fully adjusted model incorporating established CVD risk factors achieved a C-statistic of 0.852 (95% CI 0.841?0.862), with modest improvement after PAD PRS inclusion (?C-statistic 0.008). Individuals in the top 5% of the PAD PRS and top 4% of CAD PRS distribution demonstrated 3-fold greater odds of carotid stenosis. Conclusions: A PAD and CAD PRS may help identify individuals at high likelihood for carotid stenosis, though broad discriminative performance remains limited. These findings support further investigation of CVD PRSs as adjunctive risk stratification tools.