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

TL;DR

G2DR is a modular genotype-first framework that integrates genetic data, gene expression, pathways, and drug information to prioritize therapeutic targets and repurposing candidates, demonstrated through a migraine case study.

Contribution

This work introduces G2DR, a novel framework that translates genotype signals into prioritized drug targets and repurposing hypotheses without relying on disease transcriptomics.

Findings

Achieved gene-level ROC-AUC of 0.775 and PR-AUC of 0.475 in migraine case study.

Mapped prioritized genes to compounds enriched for migraine-related drugs.

Framework generalizes well to held-out data and retains biological relevance.

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.