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.
