G2DR: A Genotype-First Framework for Genetics-Informed Target Prioritization and Drug Repurposing

• URL: http://arxiv.org/abs/2603.20346v1
• Date: Fri, 20 Mar 2026 10:59:35 GMT
• Title: G2DR: A Genotype-First Framework for Genetics-Informed Target Prioritization and Drug Repurposing
• Abstract summary: Here we present G2DR, a genotype-first prioritization framework propagating inherited variation through genetically predicted expression.<n>Discovery-based prioritization generalized to held-out data, achieving gene-level ROC-AUC of 0.775 and PR-AUC of 0.475, while retaining enrichment for curated migraine biology.<n> Mapping prioritized genes to compounds via Open Targets, DGIdb, and ChEMBL yielded drug sets enriched for migraine-linked compounds relative to a global background.
• Score: 0.0
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Human genetics offers a promising route to therapeutic discovery, yet practical frameworks translating genotype-derived signal into ranked target and drug hypotheses remain limited, particularly when matched disease transcriptomics are unavailable. Here we present G2DR, a genotype-first prioritization framework propagating inherited variation through genetically predicted expression, multi-method gene-level testing, pathway enrichment, network context, druggability, and multi-source drug--target evidence integration. In a migraine case study with 733 UK Biobank participants under stratified five-fold cross-validation, we imputed expression across seven transcriptome-weight resources and ranked genes using a reproducibility-aware discovery score from training and validation data, followed by a balanced integrated score for target selection. Discovery-based prioritization generalized to held-out data, achieving gene-level ROC-AUC of 0.775 and PR-AUC of 0.475, while retaining enrichment for curated migraine biology. Mapping prioritized genes to compounds via Open Targets, DGIdb, and ChEMBL yielded drug sets enriched for migraine-linked compounds relative to a global background, though recovery favoured broader mechanism-linked and off-label space over migraine-specific approved therapies. Directionality filtering separated broadly recovered compounds from mechanistically compatible candidates. G2DR is a modular framework for genetics-informed hypothesis generation, not a clinically actionable recommendation system. All outputs require independent experimental, pharmacological, and clinical validation.

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