Polygenic risk score (PRS)

A polygenic risk score (PRS) is a weighted sum of an individual's risk-allele dosages across many SNPs associated with a trait, with weights typically derived from GWAS summary statistics using methods such as LD-pruning and thresholding (P+T) or Bayesian shrinkage (LDpred, PRSice). For common complex diseases — including coronary artery disease, type 2 diabetes, and breast cancer — high PRS identifies individuals with lifetime risk comparable to monogenic mutation carriers, suggesting clinical utility for stratified prevention. However, PRS performance degrades substantially when applied across ancestry groups because GWAS discovery cohorts have been disproportionately European, and LD patterns and allele frequencies differ between populations, limiting equitable deployment. Additional challenges include calibration drift over time, limited ability to capture rare variants and gene-environment interactions, and conceptual questions about whether PRS for longevity traits represents a useful clinical endpoint given their composite, late-acting nature.