The Parkinson's Disease Genome-Wide Association Study Locus Browser

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus.

Methods: We included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data.

Results: We created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets.

Conclusions: Our PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Keywords: GWAS; Parkinson's disease; prioritization.

FIG. 1

Flowchart of data gathered for the browser. Summary of the variants, genes, and data sets included in the browser to prioritize genes for each locus. Data sets include genome‐wide association study (GWAS) summary statistics, known coding variants (Nalls et al, 2019), ³ nominated genes, online Mendelian inheritance in man (OMIM), and human gene mutation database (HGMD) disease genes, expression quantitative trait locus data (eQTL), variants from the GWAS catalogue, known Parkinson's disease and related disorder genes, PubMed literature data, Genotype‐Tissue Expression (GTEx), and single‐cell expression data, burden test data, fine‐mapping data, and constraint data.

FIG. 2

Locus zoom and locus compare plots for locus 16 and variant rs11707416 and P2RY12. (A) Locus zoom Manhattan plot for risk variant rs11707416 on locus 16. The risk variant is uniquely colored purple, and all other variants are colored by their r ² value. Recombination rate peaks are plotted in blue. Nearby genes are included at the bottom, with P2RY12 highlighted. (B) Locus compare plots for P2RY12 on locus 16 plot –log₁₀ P values for Nalls et al (2019) GWAS data (y axis) and for different eQTL data sets (x axis). Data sets available for P2RY12 are Qi et al brain eQTL, Vosa et al blood eQTL, and PsychENCODE brain eQTL (left to right). Variants are colored by their r ² value, and the risk variant is labeled and uniquely colored purple.

FIG. 3

Bar plot for single‐cell expression of P2RY12 on locus 16. Transcript per million (TPM) data for P2RY12 was averaged across all samples for 7 cell types from the substantia nigra. These include oligodendrocyte progenitor cells (OPCs), oligodendrocyte cells (ODCs), microglia, GABAergic neurons (GABA), endothelial cells, dopaminergic neurons (DaNs), and astrocytes.

FIG. 4

Locus zoom and locus compare plots for locus 78 and variant rs2248244 and DYRK1A. (A) Locus zoom Manhattan plot for risk variant rs2248244 at locus 78. The risk variant is uniquely colored purple, and all other variants are colored by their r ² value. Recombination rate peaks are plotted in blue. Nearby genes are included at the bottom, with DYRK1A highlighted. (B) Locus compare plots for DYRK1A on locus 78 plot –log₁₀ P values for Nalls et al (2019) GWAS data (y axis) and for different eQTL data sets (x axis). Data sets available for DYRK1A are Qi et al brain eQTL, Vosa et al blood eQTL, and PsychENCODE brain isoQTL (left to right). Variants are colored by their r ² value, and the risk variant is labeled and uniquely colored purple.

FIG. 5

GTEx violin plot for DYRK1A on locus 78. DYRK1A transcript per million (TPM) data were averaged across all available samples from GTEx v8 data for different tissues. Distribution and probability of expression level are included for each tissue.