Evaluating Polygenic Score Transferability for Lipid Traits in Underrepresented Populations: Evidence from Samoan Cohorts

Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa, accounting for 34% of deaths. Polygenic scores (PGS) derived from large scale multi ancestry genome-wide association studies offer potential for improved CVD risk prediction by aggregating genetic effects on lipid traits, yet their performance in Pacific Islander populations remains largely unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL C), HDL cholesterol (HDL C), triglycerides (TG), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990 to 2010. PGS derived from Graham et al. and Kanoni et al. multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel, and performance was assessed using incremental R^2 from linear mixed models with bootstrapped confidence intervals. PGS performance varied across traits and cohorts: HDL C showed the highest performance (incremental R^2 5.0 to15.0%), followed by LDL C (5.7 to 8.6%) and TC (5.0 to10.7%), with TG showing the lowest performance (3.5 to 7.0%). Meaningful LDL C transferability was achieved only when using a genome-wide PRS CS score (99.6 to 99.7% variant matching), whereas a curated pruning-and-thresholding score achieved only ~9% matching and near-zero performance. These findings establish the first systematic benchmarks for lipid PGS performance in Samoans, demonstrate that multi-ancestry scores can achieve meaningful transferability in this underrepresented population when genome-wide variant coverage is ensured, and highlight the importance of rigorous variant harmonization assessment prior to clinical deployment of PGS in diverse populations.