Characterising the Stability of Polygenic Risk Scores: implications for risk stratification

Abstract

Polygenic risk scores (PRS) improve progressively as genome-wide association studies (GWAS) increase in sample size and ancestral diversity, yet the effect of successive GWAS releases on individual PRS rankings remains poorly characterised. Here, we quantify how individual PRS rankings change across GWAS releases, whether those changes favour cases over controls, how consistently individuals maintain their relative position, and whether those in high-risk strata retain that classification over time. Using PRS derived from four GWAS releases for bipolar disorder, major depressive disorder, and schizophrenia in three Australian cohorts, we observed widespread bidirectional reclassification that exceeded the theoretical minimum of expected reclassification, and was directionally consistent with case-control status when discriminative performance improved. Rank variability was substantial and uniformly distributed across all levels of risk, rank persistence was limited across releases, and retention of high-risk classifications was variable across disorders and largely accounted for by the inter-release correlation. These findings demonstrate that individual PRS rankings are dynamic and shaped by progressive improvements in effect-size estimates, carrying important implications for PRS-based risk stratification strategies that rely on stable classifications in psychiatric research and clinical practice.