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.

Background Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. Objectives Our aim was to examine the association between heterozygous PRKN variants, including single‐nucleotide variants and copy‐number variations (CNVs), and PD. Methods We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late‐onset (63.97 ± 7.79 years, 63% men) and 553 early‐onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next‐generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation‐dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single‐nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. Results We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely‐pathogenic heterozygous single‐nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate‐corrected P = 0.55). No associations with age at onset and in stratified analyses were found. Conclusions Heterozygous single‐nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost‐effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients. © 2020 International Parkinson and Movement Disorder Society

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.