Polygenic risk scores reveal shared polygenic risk across five common cardiovascular diseases

BACKGROUND AND AIM: The five cardiovascular diseases (CVDs): Coronary artery disease (CAD), stroke, heart failure (HF), peripheral arterial disease (PAD), and atrial fibrillation(Afib) often co-occur. Most polygenic risk scores (PRSs) are developed for individual CVDs, limiting their clinical utility across multiple CVDs. We investigated associations between five PRSs and (1) their CVDs, (2) cross-disease associations for pleiotropy, and (3) across multimorbidity clusters. METHODS: We calculated restricted PRSs using genome-wide significant variants from published genome-wide association studies and validated them in 484,154 UK Biobank participants. For the time-to-onset and sequence analysis, we included 34,394 individuals with a CAD diagnosis. We used logistic regression, Cox regression, and accelerated failure time analysis; p ≤ 0.05 was considered significant. RESULTS: had a 2.66-fold higher PAD risk (HR 2.66, 95% CI: 1.06-6.71) and developed PAD 5.6 years earlier than those in the bottom 10% (time ratio 0.40, 95% CI: 0.17-0.93). CONCLUSION: PRSs reveal shared polygenic risk across CVDs and provide insight into CVD multimorbidity trajectories, such as timing and sequence of events.