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M\u00e1laga","award":["PI13\/02434"],"award-info":[{"award-number":["PI13\/02434"]}]},{"name":"Universidad de M\u00e1laga","award":["PI16\/01861"],"award-info":[{"award-number":["PI16\/01861"]}]},{"name":"Universidad de M\u00e1laga","award":["PI17\/01474"],"award-info":[{"award-number":["PI17\/01474"]}]},{"name":"Universidad de M\u00e1laga","award":["PI19\/01240"],"award-info":[{"award-number":["PI19\/01240"]}]},{"name":"Universidad de M\u00e1laga","award":["PI19\/01301"],"award-info":[{"award-number":["PI19\/01301"]}]},{"name":"Universidad de M\u00e1laga","award":["PID2020-120463RB-I00"],"award-info":[{"award-number":["PID2020-120463RB-I00"]}]},{"name":"Universidad de M\u00e1laga","award":["POSTDOC21_00365"],"award-info":[{"award-number":["POSTDOC21_00365"]}]},{"name":"Universidad de M\u00e1laga","award":["IFI21\/00024"],"award-info":[{"award-number":["IFI21\/00024"]}]},{"name":"Universidad de M\u00e1laga","award":["FPU17\/00276"],"award-info":[{"award-number":["FPU17\/00276"]}]},{"name":"Universidad de M\u00e1laga","award":["CP19\/00068"],"award-info":[{"award-number":["CP19\/00068"]}]},{"name":"Universidad de M\u00e1laga","award":["PND2020\/048"],"award-info":[{"award-number":["PND2020\/048"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u00d7 107 single-nucleotide polymorphisms performed on Alzheimer\u2019s 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 A\u03b21-42 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms241512079","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T07:35:24Z","timestamp":1690529724000},"page":"12079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9791-7779","authenticated-orcid":false,"given":"Alvaro","family":"Esteban-Martos","sequence":"first","affiliation":[{"name":"Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s\/n, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Brokate-Llanos","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular e Ingenier\u00eda Bioqu\u00edmica, Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO\/CSIC\/JA, Ctra Utrera Km1, 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4932-7429","authenticated-orcid":false,"given":"Luis Miguel","family":"Real","sequence":"additional","affiliation":[{"name":"Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s\/n, 29071 Malaga, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6335-2685","authenticated-orcid":false,"given":"Sonia","family":"Melgar-Locatelli","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain"},{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2148-381X","authenticated-orcid":false,"given":"Itziar","family":"de Rojas","sequence":"additional","affiliation":[{"name":"Research Center and Memory Clinic, Ace Alzheimer Center Barcelona\u2014Universitat Internacional de Catalunya, 08017 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Castro-Zavala","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain"},{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jose","family":"Bravo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s\/n, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria del Carmen","family":"Ma\u00f1as-Padilla","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain"},{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Garc\u00eda-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Research Center and Memory Clinic, Ace Alzheimer Center Barcelona\u2014Universitat Internacional de Catalunya, 08017 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximiliano","family":"Ruiz-Galdon","sequence":"additional","affiliation":[{"name":"Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s\/n, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Pacheco-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain"},{"name":"Unidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Polvillo","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular e Ingenier\u00eda Bioqu\u00edmica, Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO\/CSIC\/JA, Ctra Utrera Km1, 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5795","authenticated-orcid":false,"given":"Fernando","family":"Rodriguez de Fonseca","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain"},{"name":"Unidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s\/n, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-1167","authenticated-orcid":false,"given":"Estela","family":"Castilla-Ortega","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain"},{"name":"Departamento de 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