| アブストラクト | Safety-related issues account for approximately 25% of failures in new drug discovery programs. On top of that, many are discovered during post-marketing surveillance, significantly limiting drug utility and application. To proactively address these concerns, we developed a genetics-led strategy leveraging Mendelian Randomization (MR) across large-scale genetic datasets from the Million Veteran Program, FinnGen, and UK Biobank. By mapping genetic variants associated with gene expression and protein abundance to 1,449 harmonized human phenotypes, we systematically identified potential adverse drug reactions (ADR). Our extensive MR analysis, encompassing 16,915 protein-coding genes, demonstrated the capacity to predict hundreds of known ADR for approved medications, with approximately 40% corroborated by FDA Adverse Event Reporting System (FAERS) data. Additionally, we found significant enrichment of identified gene-mechanism pairs in clinical trials terminated early due to safety concerns, highlighting the clinical utility of genetics-informed safety prediction. Notably, immune-related pathways were prominently associated with ADR, indicating particular sensitivity within immune modulation targets. Our comprehensive atlas, integrating genetic evidence with pharmacological mechanisms, provides a robust predictive framework for anticipating drug safety, potentially enhancing decision-making in drug development and pharmacovigilance. An interactive web interface allowing filtering by gene, phenotype, drug phase, and mechanism of action is available at https://shiny.parse-health.org/safety/. |
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| 投稿者 | Ferolito, Brian R; Horimoto, Andrea R V R; Gravel-Pucillo, Kai; Golden, Daniel J; Dashti, Hesam; Giambartolomei, Claudia; Rasooly, Danielle; Matty, Rachael; Gaziano, Liam; Tsepilov, Yakov; Costa, Lauren; Kosik, Nicole; Ioannidis, Harris; Karim, Mohd; Winicki, Giovanna; Hunter, Fiona; Langenberg, Claudia; Whittaker, John C; Cai, Tianxi; Peloso, Gina M; Zdrazil, Barbara; Ghoussaini, Maya; Leach, Andrew R; Muralidhar, Sumitra; Smit, Ines A; Casas, Juan P; Gaziano, J Michael; Cho, Kelly; Pereira, Alexandre C |
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| 組織名 | Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare;System, Boston, Massachusetts, United States of America.;Department of Genetics, University of North Carolina School of Medicine, Chapel;Hill, North Carolina, United States of America.;Division of Aging, Brigham and Women's Hospital and Harvard Medical School,;Boston, Massachusetts, United States of America.;The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad;Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.;Health Data Science Centre, Human Technopole, Milan, Italy.;Centre for Human Technologies (CHT), Istituto Italiano di Tecnologia, Genova,;Italy.;BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United;Kingdom.;Open Targets Genetics, Open Targets, Hinxton, United Kingdom.;European Molecular Biology Laboratory, European Bioinformatics Institute,;Hinxton, United Kingdom.;Genomic Discovery, Variant Bio, Seattle, Washington, United States of America.;Precision Healthcare University Research Institute, Queen Mary University of;London, London, United Kingdom.;Computational Medicine, Berlin Institue of Health at Charit e -;Universitatsmedizin, Berlin, Germany.;MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.;MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.;Department of Biomedical Informatics, Harvard Medical School, Boston,;Massachusetts, United States of America.;Department of Biostatistics, Boston University School of Public Health, Boston,;Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, United;States of America.;LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, United Kingdom.;Department of Veterans Affairs, Office of Research and Development, Washington;District of Columbia, United States of America.;Biomarker Development/Translational Medicine, Novartis Institutes for Biomedical;Research, Cambridge, Massachusetts, United States of America.;Department of Medicine, Harvard Medical School, Boston, Massachusetts, United |
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