Genetic evidence informs the direction of therapeutic modulation in drug development.

ABSTRACT: Determining the correct direction of effect (DOE), whether to increase or decrease the activity of a drug target, is essential for therapeutic success. We introduce a framework to predict DOE at gene and gene-disease levels using gene and protein embeddings and genetic associations across the allele frequency spectrum, respectively. Specifically, we predict: (1) DOE-specific druggability for 19,450 protein-coding genes with a macro-averaged area under the receiver operating characteristic curve (AUROC) of 0.95; (2) isolated DOE among 2553 druggable genes with a macro-averaged AUROC of 0.85; and (3) gene-disease-specific DOE for 47,822 gene-disease pairs with a macro-averaged AUROC of 0.59, with performance improving with genetic evidence availability. Our predictions outperform existing ap

SUBMITTER: Chen R 

PROVIDER: S-EPMC12488494 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature