Prioritizing Parkinson’s disease risk genes in genome-wide association loci
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.
Authors
- Catalina Cerquera Cleves
- Georgia Panagiotaropoulou (ORCID: https://orcid.org/0000-0001-9516-6158)
- Marijn Schipper (ORCID: https://orcid.org/0000-0002-5170-2796)
- Nathaniel Bell
- Julia Kraft (ORCID: https://orcid.org/0000-0001-7306-1179)
- Stephan Ripke (ORCID: https://orcid.org/0000-0003-3622-835X)
- Lara Mariah Lange (ORCID: https://orcid.org/0000-0002-7162-9821)
- Daniëlle Posthuma (ORCID: https://orcid.org/0000-0001-7582-2365)
- Karl Heilbron (ORCID: https://orcid.org/0000-0003-4776-1723)
- Cornelis Blauwendraat (ORCID: https://orcid.org/0000-0001-9358-8111)
- Swapnil Awasthi (ORCID: https://orcid.org/0000-0002-9692-8123)
- Alice Braun
Institutions
- Broad Institute (US)
- National Institutes of Health (US)
- Centre hospitalier universitaire de Québec (CA)
- Amsterdam Neuroscience (NL)
- National Institute of Neurological Disorders and Stroke (US)
- National Institute on Aging (US)
- Centre hospitalier de l'Université Laval (CA)
- Hospital Universitario San Ignacio (CO)
- Charité - Universitätsmedizin Berlin (DE)
- Vrije Universiteit Amsterdam (NL)
- University of Lübeck (DE)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1038/s41531-025-00933-0
- Citations
- 7
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 9.72
Funders
- Alexander von Humboldt-Stiftung
- European Commission
- Deutsche Forschungsgemeinschaft
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute on Aging
- National Institute of Mental Health