Abstract
BACKGROUND: Polygenic risk score (PRS) quantifies the cumulative effects of common genetic variants across the genome, including both coding and non-coding regions, to predict the risk of developing common diseases. In cardiovascular medicine, PRS enhances risk stratification beyond traditional clinical risk factors, offering a precision medicine approach to coronary artery disease (CAD) prevention. This study evaluates the predictive performance of a multi-ancestry PRS framework for cardiovascular risk assessment using the All of Us (AoU) short-read whole-genome sequencing dataset comprising over 225,000 participants. METHODS: We developed PRSs for lipid traits (LDL-C, HDL-C, triglycerides) and cardiometabolic conditions (type 2 diabetes, hypertension, atrial fibrillation) and constructed two metaPRSs: one integrating lipid and cardiometabolic PRSs (risk factor metaPRS) and another incorporating CAD PRSs in addition to these risk factors (risk factor + CAD metaPRS). Predictive performance was evaluated separately for each trait-specific PRS and for both metaPRSs to assess their effectiveness in CAD risk prediction across diverse ancestries. Model predictive performance, including calibration, was assessed separately for each ancestry group, ensuring that all metrics were ancestry-specific and that PRSs remain generalizable across diverse populations Results: PRSs for lipids and cardiometabolic conditions demonstrated strong predictive performance across ancestries. The risk factors metaPRS predicted CAD risk across multiple ancestries. The addition of a CAD-specific PRS to the risk factors metaPRS improved predictive performance, highlighting a genetic component in CAD etiopathology that is not fully captured by traditional risk factors, whether clinically measured or genetically inferred. Model calibration and validation across ancestries confirmed the broad applicability of PRS-based approaches in multi-ethnic populations. CONCLUSION: PRS-based risk stratification provides a reliable, ancestry-inclusive framework for personalized cardiovascular disease prevention, enabling better targeted interventions such as pharmacological therapy and lifestyle modifications. By incorporating genetic information from both coding and non-coding regions, PRSs refine risk prediction across diverse populations, advancing the integration of genomics into precision medicine for common diseases.