Category: Parkinson's Disease: Genetics
Objective: (1) Evaluation of lyso-PRS performance for PD status across diverse populations; (2) Comparison of the lyso-PRS across idiopathic PD (iPD), GBA1-PD, non-manifesting GBA1 carriers (NMC), and healthy controls (HC) in the European population and assessment of the lyso-PRS association with GBA1-PD status.
Background: Lysosomal dysfunction has been implicated in Parkinson’s disease (PD) pathogenesis. Pathway polygenic risk scores (PRS) aggregate single nucleotide polymorphisms (SNPs) effects within biologically defined pathways to quantify pathway-specific genetic risk. However, lysosomal polygenic risk scores (lyso-PRS) have not been evaluated extensively in PD across populations.
Method: We analyzed Neurobooster array (NBA) data from the Global Parkinson’s Disease Genetic Program, including 33,821 iPD cases and 19,875 healthy controls across 10 ancestries and PRS were generated using PRSice with the default clumping-and-thresholding approach (r² = 0.1, 250 kb window). We used European-NBA for training and European-TUEPAC for validation. In the European cohort, we compared lyso-PRS across GBA1-PD (N = 2,092) versus NMC (N = 477), 23,607 iPD (N = 23,607), and HC (N = 10,029).
Results: (1) Lyso-PRS showed modest discrimination of iPD status, performing best in Europeans (European-NBA test cohort: AUC = 0.60, p = 5.05e-173; European-TUEPAC validation cohort: AUC = 0.63, p = 5.34e-20) and worse in other populations (AUC: 0.51-0.59, p<0.05), with no significance in the African American (AAC) population. (2) In the European cohort, the lyso-PRS distinguished GBA1-PD from HC (AUC = 0.62, p = 3.80e-67) and from NMC (AUC = 0.62, p = 1.86e-17), but not from iPD (AUC = 0.51).
Conclusion: Lyso-PRS was associated with iPD and GBA1-PD status, with the strongest predictive performance in the European population, underscoring the need to improve accuracy in other ancestries.
To cite this abstract in AMA style:
W. Sun, K. Brockmann, C. Schulte, T. Gasser, M. Tan. Lysosomal polygenic risk score in Parkinson disease across populations. [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/lysosomal-polygenic-risk-score-in-parkinson-disease-across-populations/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/lysosomal-polygenic-risk-score-in-parkinson-disease-across-populations/