GeneSIS: enhancing transferability of polygenic scores with variant-level gene-by-sex interaction effects
Year: 2026
Type: preprint
Abstract: 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.
Authors: Yosuke Tanigawa, Manolis Kellis
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Epigenomic, transcriptional and cellular dissection of Alzheimer's variants, Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related Dementias, Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease, Single Cell Transcriptional and Epigenomic Dissection of Schizophrenia and Bipoloar Disease, Interpreting non-coding variants using epigenomics, regulatory models, & validation experiments, Construction of an Integrated Immune - Vascular Brain - Chip as a Platform for the Study, Drug Screening, and Treatments of Alzheimer's Disease, Cell type specific epigenetic analysis to understand complex mechanisms underlying Alzheimer's disease phenotypes, Network-based prediction and validation of causal schizophrenia genes and variants, Single-cell multi-region transcriptional and epigenomic dissection of VCID., Dissection of endosomal trafficking mechanisms in Alzheimer's Disease, Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease, Single-Cell Transcriptional and Epigenomic Dissection to Identify Therapeutic Targets for ALS and FTD, G9000114869, G9000326702, Identification of TDP-43 Modifiers Through Single-Cell Transcriptional and Epigenomic Dissection of ALS and FTLD-MND, Single-cell multi-region dissection of AD-pathogen interactions for HSV-1 and CMV, Single Cell Transcriptomic and Epigenomic Dissection of Opioid and Cocaine Responses in HIV, Single-cell multi-region transcriptional and epigenomic dissection of VCID., Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease, Single-Cell Transcriptional and Epigenomic Dissection to Identify Therapeutic Targets for ALS and FTD, Mapping the vulnerable locus coeruleus pathways in aging and AD
OpenAlex ID: W7213497896