{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:32:07Z","timestamp":1786375927909,"version":"build-2736575974"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Queensland and the Baker Heart and Diabetes Institute"},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["GRNT2041888"],"award-info":[{"award-number":["GRNT2041888"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NVIDIA Academic Grant Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human genetics offers a scalable route to therapeutic discovery, but practical frameworks that convert genotype-derived signal into ranked target and drug hypotheses remain limited, particularly when matched disease transcriptomics are unavailable. We present G2DR, a genotype-first computational prioritization framework that integrates genetically predicted gene expression, multi-method gene-level testing, pathway enrichment, network context, druggability, and multi-source drug\u2013target evidence to generate hypotheses for downstream follow-up. In a migraine case study of 733 UK Biobank participants (53 cases, 680 controls) using stratified five-fold cross-validation, G2DR imputed genetically regulated expression across seven transcriptome-weight resources and ranked genes using a reproducibility-aware discovery score derived only from training and validation data, followed by a balanced integrated score for target selection. Internal held-out evaluation within the same UK Biobank-derived analytical framework achieved gene-level ROC\u2013AUC of 0.775 and PR-AUC of 0.475 for recovery of test-significant genes, while retaining enrichment for curated migraine-associated biology. Mapping prioritized genes to compounds through Open Targets, DGIdb, and ChEMBL produced drug sets enriched for migraine-linked and literature-associated compounds relative to a global drug background. However, tiered benchmarking showed limited recovery of migraine-specific approved therapies, with stronger signal from mechanism-linked, off-label, and literature-associated pharmacological space. Directionality filtering further distinguished broadly recovered compounds from those with stronger mechanistic compatibility. G2DR is, therefore, best viewed as a modular framework for genetics-informed hypothesis generation in genotype-first settings, not as a clinically actionable target-identification or drug-recommendation system. Prioritized genes and compounds require independent validation.<\/jats:p>","DOI":"10.1093\/bib\/bbag427","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:45:22Z","timestamp":1784288722000},"source":"Crossref","is-referenced-by-count":0,"title":["G2DR: a genotype-first framework for genetics-informed target prioritization and drug repurposing"],"prefix":"10.1093","volume":"27","author":[{"given":"Muhammad","family":"Muneeb","sequence":"first","affiliation":[{"name":"School of Chemistry and Molecular Biology, The University of Queensland , Queen Street, 4067 Queensland ,","place":["Australia"]},{"name":"Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute , Commercial Road, 3004 Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B","family":"Ascher","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biology, The University of Queensland , Queen Street, 4067 Queensland ,","place":["Australia"]},{"name":"Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute , Commercial Road, 3004 Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"2026081011263008000_ref1","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat Rev Drug Discov"},{"key":"2026081011263008000_ref2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat Rev Drug 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