GeneSIS: enhancing transferability of polygenic scores with variant-level gene-by-sex interaction effects

Advancing precision medicine requires accurate prediction of disease liability across populations and contexts. A major challenge is the limited transferability of polygenic scores (PGS) across genetic ancestry groups. We present GeneSIS (GENE and Sex Interaction Score), a supervised statistical learning framework for jointly modeling additive and context-dependent genetic effects at single-variant resolution directly from individual-level data. We analyze 406,659 individuals, including admixed individuals, in the UK Biobank and 1.3 million variants to develop predictive models for 99 complex traits. We report that ~8% of selected variables capture gene-by-sex (GxS) effects, validated by sex-stratified analyses. Modeling GxS effects improves prediction across 32 traits in non-European individuals. For predicting hip circumference in Africans, GeneSIS achieves a 3.7-fold improvement (p=8.0×10⁻⁷) over linear-only PGS and highlights biologically plausible hypotheses, such as pleiotropic GxS effects of GCKR (rs1260326) on anthropometry and menopause, as well as GxS pathway enrichments for interleukin-4 regulation. Overall, our results highlight the benefits of integrating context-dependent effects in human genetics studies.