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Finding genetically-supported drug targets for Parkinson´s disease using Mendelian randomization of the druggable genome

Abstract: Parkinson´s disease is a neurodegenerative movement disorder that currently has no diseasemodifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson?s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson?s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson?s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson?s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson?s disease drug development.

 Fuente: Nature Communications 12, 7342 (2021)

 Editorial: Nature Publishing Group

 Fecha de publicación: 01/12/2021

 Nº de páginas: 14

 Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41467-021-26280-1

 ISSN: 2041-1723

 Url de la publicación: https://doi.org/10.1038/s41467-021-26280-1

Autoría

STORM, CATHERINE S.

KIA, DEMIS A.

ALMRAMHI, MONA M.

BANDRES-CIGA, SARA

FINAN, CHRIS

HINGORANI, AROON D.

WOOD, NICHOLAS W.