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Background Lysosomal dysfunction has been implicated in Parkinson’s disease (PD) pathogenesis. However, lysosomal polygenic risk scores (lyso-PRS) have not been evaluated extensively in PD across populations. Objectives (1) Evaluation of lyso-PRS (lyso-PRS) performance for PD risk across populations; (2) Comparison of lyso-PRS across idiopathic PD (iPD), GBA1 -PD, non-manifesting GBA1 carriers (NMC), and healthy controls (HC) in the European population. (3) Assessment of the lyso-PRS association with clinical outcomes in the PD patients of European population. Methods We analyzed Neurobooster array data from the Global Parkinson’s Genetics Program (GP2) dataset, including 32,054 iPD cases and 18,188 healthy controls across ten ancestries. Results (1) lyso-PRS performed best in Europeans (European-GP2 test cohort: AUC = 0.602, p = 2.02e-172; European-TUEPAC validation cohort: AUC = 0.632, p = 5.34e-20) and worse in other populations (AUC: 0.51-0.59, pConclusions 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. In the European population, the lyso-PRS showed associations with clinical features; however, not all findings were replicated in the validation cohort, highlighting the need for further investigation in large and diverse cohorts.
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