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As drug targets with genetic support have a doubled success rate, genetics-informed drug repurposing holds promise in translating genetic findings into therapeutics. In this study, we developed a Genetics Informed Network-based Drug Repurposing via in silico Perturbation (GIN-DRIP) framework and applied the framework to repurpose drugs for type-2 diabetes (T2D). In GIN-DRIP for T2D, it integrates multi-level omics data to translate T2D GWAS signals into a genetics-informed network that simultaneously encodes gene importance scores and a directional effect (up\/down) of risk genes for T2D; it then bases on the GIN to perform signature matching with drug perturbation experiments to identify drugs that can counteract the effect of T2D risk alleles. With this approach, we identified 3 high-confidence FDA-approved candidate drugs for T2D, and validated telmisartan, an anti-hypertensive drug, in our EHR data with over 3 million patients. We found that telmisartan users were associated with a reduced incidence of T2D compared to users of other anti-hypertensive drugs and non-users, supporting the therapeutic potential of telmisartan for T2D. Our framework can be applied to other diseases for translating GWAS findings to aid drug repurposing for complex diseases.<\/jats:p>","DOI":"10.1101\/2025.03.22.25324223","type":"posted-content","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T02:07:01Z","timestamp":1742782021000},"source":"Crossref","is-referenced-by-count":2,"title":["A Genetics-guided Integrative Framework for Drug Repurposing: Identifying Anti-hypertensive Drug Telmisartan for Type 2 Diabetes"],"prefix":"10.64898","author":[{"given":"Xue","family":"Zhong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshul","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingshan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025032600350998000_2025.03.22.25324223v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/acr2.11114"},{"key":"2025032600350998000_2025.03.22.25324223v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2019.107843"},{"key":"2025032600350998000_2025.03.22.25324223v1.3","unstructured":"International Diabetes Federation. 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