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 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.

Fig. 1. Overview of MR and our study.

a Genetic variants associated with the expression of a gene are called eQTLs, and they mimic life-long exposure to higher or lower levels of gene expression (the exposure). These variants affect PD (the outcome) through the exposure only, i.e. there is no horizontal pleiotropy. b MR is analogous to a randomized controlled trial, where individuals are randomly allocated to a genotype according to Mendel’s law of independent assortment. c Workflow and summarized results of our MR study. eQTL expression quantitate trait locus, MR Mendelian randomization, PD Parkinson’s disease, pQTL protein quantitative trait locus.

Fig. 2. Fifteen potential preventative drug targets reach significance in two independent PD case-control cohorts.

Forest plots showing the discovery-phase results for the 15 replicated genes. The centre of the error bars represents the PD odds ratio per 1-standard-deviation increase in gene expression, calculated using the Wald ratio (if 1 SNP) or IVW (if >1 SNP) and corrected for the number of genes tested. Results are colour-coded according to the tissue (red = blood, blue = brain tissue). 95% CI 95% confidence interval, FDR false discovery rate, OR odds ratio, PD Parkinson’s disease.

Fig. 3. Four potential preventative drugs may also affect PD age at onset.

Forest plot; the centre of the error bars represents the standard-deviation change in PD age at onset per 1-standard-deviation increase in gene expression, calculated using the Wald ratio (if 1 SNP) or IVW (if >1 SNP) and colour-coded by tissue (red = blood, blue = brain tissue). A negative beta corresponds to a younger age at onset, and a positive beta corresponds to an older age at onset. 95% CI 95% confidence interval, PD Parkinson’s disease.

Fig. 4. Genetically-predicted expression of eight genes in blood or brain tissue is associated with PD progression markers.

Forest plot; the centre of the error bars show the standard-deviation change in each progression marker, per 1-standard-deviation increase in gene expression, calculated using the Wald ratio (if 1 SNP) or IVW (if >1 SNP). Results are colour-coded by tissue (red = blood, blue = brain tissue) and corrected for the number of genes tested. 95% CI 95% confidence interval, DEPR depression, FDR false discovery rate, HY Hoehn and Yahr, DEPR depression, UPDRS2-4 Unified Parkinson’s Disease Rating Scale parts 2 to 4.

Fig. 5. Protein quantitative trait loci in blood provide further genetic evidence.

Forest plots showing the results for all proteins and outcomes where a pQTL was available. The centre of the error bars show the (a) PD odds ratio and (b) standard-deviation change in UPDRS part 4 score, per 1-standard-deviation increase in circulating protein levels, calculated using the Wald ratio (if 1 SNP) or IVW (if >1 SNP). The “pQTL Source” column indicates which pQTL study the SNPs were derived from. 95% CI 95% confidence interval, OR odds ratio, PD Parkinson’s disease, pQTL protein quantitative trait locus, UPDRS Unified Parkinson’s Disease Rating Scale.