Abstract
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 All PRSs were significantly associated with their respective CVDs (ORs 1.08-1.60 per 1-SD). The odds of CAD increased by 55% per 1-SD increase in PRSCAD (OR 1.55, 95% CI: 1.53-1.57). In cross-disease associations, all 25 PRS-CVD pairs were significant. For some CVDs, PRS from other CVDs showed a stronger association than their own. For instance, HF was more strongly associated with PRSAfib than PRSHF (OR 1.21 vs 1.17). In CAD patients, those in the top 10% of PRSCAD 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.