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00925njm 22002777a 4500 dc Esteban-Martos, Alvaro author Brokate-Llanos, Ana María author Real-Navarrete, Luis Miguel author Melgar-Locatelli, Sonia author De Rojas, Itziar author Castro-Zavala, Adriana author Bravo-Romero, María José author Mañas-Padilla, María del Carmen author García-González, Pablo author Ruiz-Galdón, Maximiliano author Pacheco-Sánchez, Beatriz author Polvillo, Rocío author Rodriguez-de-Fonseca, Fernando author González, Irene author Castilla-Ortega, María Estela author Muñoz-Gómez, Manuel author Rivera-González, Patricia author Reyes-Engel, Armando author Ruiz, Agustín author Royo-Sánchez-Palencia, José Luis author 2023 Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases. Esteban-Martos, A., Brokate-Llanos, A. M., Real, L. M., Melgar-Locatelli, S., de Rojas, I., Castro-Zavala, A., ... & Royo, J. L. (2023). A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease. International Journal of Molecular Sciences, 24(15), 12079. https://hdl.handle.net/10630/28761 10.3390/ijms241512079 A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease