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Recent advancements in Parkinson's disease (PD) drug development have been significantly driven by genetic research. Importantly, drugs supported by genetic evidence are more likely to be approved. While genome-wide association studies (GWAS) are a powerful tool to nominate genomic regions associated with certain traits or diseases, pinpointing the causal biologically relevant gene is often challenging. Our aim was to prioritize genes underlying PD GWAS signals. The polygenic priority score (PoPS) is a similarity-based gene prioritization method that integrates genome-wide information from MAGMA gene-level association tests and more than 57,000 gene-level features, including gene expression, biological pathways, and protein-protein interactions. We applied PoPS to data from the largest published PD GWAS in East Asian- and European-ancestries. We identified 120 independent associations with P < 5×10 -8 and prioritized 46 PD genes across these loci based on their PoPS scores, distance to the GWAS signal, and presence of non-synonymous variants in the credible set. Alongside well-established PD genes ( e.g., TMEM175 and VPS13C ), some of which are targeted in ongoing clinical trials ( i.e ., SNCA , LRRK2 , and GBA1 ), we prioritized genes with a plausible mechanistic link to PD pathogenesis ( e.g., RIT2, BAG3 , and SCARB2 ). Many of these genes hold potential for drug repurposing or novel therapeutic developments for PD ( i.e., FYN, DYRK1A, NOD2, CTSB, SV2C , and ITPKB ). Additionally, we prioritized potentially druggable genes that are relatively unexplored in PD ( XPO1, PIK3CA, EP300, MAP4K4, CAMK2D, NCOR1 , and WDR43 ). We prioritized a high-confidence list of genes with strong links to PD pathogenesis that may represent our next-best candidates for disease-modifying therapeutics. We hope our findings stimulate further investigations and preclinical work to facilitate PD drug development programs., Competing Interests: Competing interests LML, CCC, JK, AB, SA, GP, MS, NB, DP, SR and CB have nothing to disclose. KH is a former employee of 23andMe, Inc. and a current employee of Bayer AG.

Multiple scientific studies, mostly performed within European populations, have unraveled many of the genetic factors associated with Alzheimer's disease (AD) and Parkinson's disease (PD) etiologies, improving our understanding of the molecular pathways implicated in the pathogenesis of these conditions. However, there is increasing evidence that the genetic architecture of these diseases differs across ancestral populations. This raises concerns about the efficacy of therapeutic interventions crafted around genetic targets prevalent only in European ancestry populations. Such interventions neglect potentially distinctive etiological profiles, including Latino, Black/African American, and East Asian populations. In the current study, we explore Population Attributable Risk (PAR) in AD and PD etiologies and assess the proportion of disease attributed to specific genetic factors across diverse populations. Leveraging data from genome-wide association studies across four ancestries, we explore distinct and universal therapeutic targets across diverse populations. Multi-ancestral genetics research is critical to the development of successful therapeutics and treatments for neurodegenerative diseases. By offering insights into genetic disparities, we aim to inform more inclusive and effective therapeutic strategies, advancing personalized healthcare., Competing Interests: Conflicts of interest: L.J., H.I, M.B.M, and M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board at Clover Therapeutics and is an advisor and scientific founder at Neuron23 Inc.