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

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International Parkinson’s Disease Genomics Consortium (IPDGC) , Storm , C S , Kia , D A , Almramhi , M M , Bandres-Ciga , S , Finan , C , Hingorani , A D , Wood , N W , Majamaa , K , Siitonen , A & Tienari , P 2021 , ' Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome ' , Nature Communications , vol. 12 , no. 1 , 7342 . https://doi.org/10.1038/s41467-021-26280-1

Title: Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome
Author: International Parkinson’s Disease Genomics Consortium (IPDGC); Storm, Catherine S.; Kia, Demis A.; Almramhi, Mona M.; Bandres-Ciga, Sara; Finan, Chris; Hingorani, Aroon D.; Wood, Nicholas W.; Majamaa, Kari; Siitonen, Ari; Tienari, Pentti
Contributor organization: HUS Neurocenter
Department of Neurosciences
Clinicum
Date: 2021-12-20
Language: eng
Number of pages: 14
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-021-26280-1
URI: http://hdl.handle.net/10138/341395
Abstract: There is currently no disease-modifying treatment for Parkinson's disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson's disease using Mendelian randomization of the druggable genome. Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying 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.
Subject: 3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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