Prioritizing Parkinson's disease risk genes in genome-wide association loci

Abstract

Many drug targets in ongoing Parkinson's disease (PD) clinical trials have strong genetic links. While genome-wide association studies (GWAS) nominate regions associated with disease, pinpointing causal genes is challenging. Our aim was to prioritize additional druggable genes underlying PD GWAS signals. The polygenic priority score (PoPS) integrates genome-wide information from MAGMA gene-level associations and over 57,000 gene-level features. We applied PoPS to East Asian and European PD GWAS data and prioritized genes based on PoPS, distance to the GWAS signal, and non-synonymous credible set variants. We prioritized 46 genes, including well-established PD genes (SNCA, LRRK2, GBA1, TMEM175, VPS13C), genes with strong literature evidence supporting a mechanistic link to PD (RIT2, BAG3, SCARB2, FYN, DYRK1A, NOD2, CTSB, SV2C, ITPKB), and genes relatively unexplored in PD. Many hold potential for drug repurposing or development. We prioritized high-confidence genes with strong links to PD pathogenesis that may represent our next-best candidates for developing disease-modifying therapeutics.

Fig. 1. Heatmap of prioritized Parkinson’s disease genes.

An overview of the evidence supporting each prioritized gene sorted by gene name. Distance: distance in kilobases between gene and credible set. PoPS: PoPS percentile where 0 represents the smallest genome-wide value and 1 represents the largest. MAGMA: # genes: number of genes in the locus. L2G: Probability of being the causal genes according to the L2G model. Yu2024: Probability of being the causal genes according to the Yu2024 model.

Fig. 2. Variant-level associations and PoPS results for selected loci.

The upper portion of each sub-plot is a LocusZoom plot. Each point represents a different genetic variant, the x-axis represents physical position on the listed chromosome, the left y-axis represents –log₁₀-transformed P value, the right y-axis represents the recombination rate, color represents linkage disequilibrium with the lead variant in the locus (as shown in the legend), and the horizontal dashed line represents the genome-wide significance P value threshold of 5 × 10^–8. The lower portion of each figure is a PoPS plot. Genes are denoted as blue bars spanning from their transcription start site to their transcription stop site using the same x-axis as the LocusZoom plot, the y-axis represents the raw PoPS score, the dashed horizontal gray lines represent the top 10% and 1% of PoPS scores genome-wide, and the solid horizontal gray line represents a PoPS score of 0.

Fig. 3. Small molecule target tractability assessment.

Predicted tractability of the 38 prioritized genes that are not already targets of approved or investigational drugs. Data was extracted from the Open Targets platform using GraphQL API queries (https://platform.opentargets.org/) (see Methods). Various forms of evidence that suggest that a target may be tractable are shown on the x-axis, sorted from highest-quality to lowest. Structure with Ligand: a Protein Data Bank co-crystal structure exists for the target and a small molecule. High-Quality Ligand: the target is bound by a ligand that (1) has a property forecast index ≤7, (2) binds ≤2 distinct protein domains and motifs identified by SMART (Simple Modular Architecture Research Tool), and (3) is derived from ≥2 distinct chemical scaffolds. High-Quality Pocket: the target has a DrugEBIlity score ≥0.7. Med-Quality Pocket: the target has a DrugEBIlity score 0–0.7. Druggable Family: the target was reported to be a member of the druggable genome in Finan et al. . Light green cells indicate that a given gene is supported by a given form of evidence, while dark green cells indicate an absence of such evidence. For more information on ongoing targeted drug trials for a selection of genes, see Supplementary Table 3.