Locus-specific gene-context interactions improve polygenic prediction

Polygenic scores (PGS) are a primary output of large-scale genetic studies and are being deployed in clinical and non-clinical settings. However, current PGS assume simple additive models that ignore context-specific genetic effects, which likely reduce their accuracy and robustness. To address this, we developed PGSC, a PGS framework to incorporate locus-specific gene-context interaction effects (GxC). Simulations show PGSC is robust under the additive model and outperforms PGS in realistic settings. Using sex, age, and statin treatment status as contexts in UK Biobank, we find that PGSC outperforms PGS on average across 48 traits, with substantial improvement in some cases, such as GxSex for testosterone, GxAge for bilirubin, and GxStatins for LDL cholesterol. PGSC consistently outperforms a simple genome-wide GxC model, ampPGS, which only outperforms PGS when a context uniformly amplifies all genome-wide additive effects. Critically, PGSC improvements replicate across ancestries in the UK Biobank and in an external cohort, the Mount Sinai Million Health Discovery Program. Finally, we test robustness to log-scale phenotypes and find that ampPGS gains vanish, while the locus-specific GxC components in PGSC persist. Overall, PGSC is a simple, robust framework that demonstrates GxC effects can improve out-of-sample PGS prediction and is a step toward precision treatment.