Polygenic Risk Score for Coronary Artery Disease in the Yoruba Population: Derivation and Validation in Oyo and Osun States

Polygenic risk scores (PRS) aggregate small-effect genetic variants across the genome to estimate individual disease risk and hold promise for clinical risk stratification. Most existing PRS for coronary artery disease (CAD) are derived from European GWAS and show reduced performance in African ancestry populations due to differences in linkage disequilibrium and allele frequencies. This study derived and validated a CAD polygenic risk score in the Yoruba population using genome-wide data from patients in Oyo and Osun States, South West Nigeria. Three hundred Yoruba adults with confirmed CAD by angiography or ECG-validated myocardial infarction and 300 healthy controls were enrolled. Genome-wide SNP data were generated using the H3Africa array. A Yoruba-specific PRS was derived using LDpred2, incorporating summary statistics from the African Descent and Coronary Artery Disease (ADADC) GWAS as the base dataset. The PRS was validated using 10-fold cross-validation and compared with the established metaGRS PRS derived from European populations. The Yoruba-derived PRS significantly outperformed the European metaGRS in this cohort, particularly at the tails of the risk distribution. PRS addition to traditional clinical risk factors significantly improved CAD risk prediction. These findings support population-specific PRS derivation for cardiovascular risk in Yoruba Nigerians. Keywords: polygenic risk score, coronary artery disease, Yoruba, H3Africa, cardiovascular genetics