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| Format: | Preprint |
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2026
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| Accès en ligne: | https://arxiv.org/abs/2603.20346 |
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| _version_ | 1866914412169789440 |
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| author | Muneeb, Muhammad Ascher, David B. |
| author_facet | Muneeb, Muhammad Ascher, David B. |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2603_20346 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | G2DR: A Genotype-First Framework for Genetics-Informed Target Prioritization and Drug Repurposing Muneeb, Muhammad Ascher, David B. Genomics Machine Learning 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. |
| title | G2DR: A Genotype-First Framework for Genetics-Informed Target Prioritization and Drug Repurposing |
| topic | Genomics Machine Learning |
| url | https://arxiv.org/abs/2603.20346 |