Performance of deep-learning-based approaches to improve polygenic scores.

Martin Kelemen; Yu Xu; Tao Jiang; Jing Hua Zhao; Carl A Anderson; Chris Wallace; Adam Butterworth; Michael Inouye
Abstract
Polygenic scores, which estimate an individual's genetic propensity for a disease or trait, have the potential to become part of genomic healthcare. Neural-network based deep-learning has emerged as a method of intense interest to model complex, nonlinear phenomena, which may be adapted to exploit gene-gene and gene-environment interactions to potentially improve polygenic scores. We fit neural-network models to both simulated and 28 real traits in the UK Biobank. To infer the amount of nonlinearity present in a phenotype, we also present a framework using neural-networks, which controls for the potential confounding effect of linkage disequilibrium. Although we found evidence for small amounts of nonlinear effects, neural-network models were outperformed by linear regression models for both genetic-only and genetic+environmental input scenarios. In this work, we find that the usefulness of neural-networks for generating polygenic scores may currently be limited and confounded by joint tagging effects due to linkage disequilibrium.
Journal NATURE COMMUNICATIONS
ISSN 2041-1723
Published 02 Jun 2025
Volume 16
Issue 1
Pages 5122
DOI 10.1038/s41467-025-60056-1
Type Journal Article
Sponsorship