Common variants in the lysosomal pathway contribute to Parkinson's Disease risk

Objective Despite the progress in identifying an ever-increasing number of genetic loci implicated in Parkinson’s disease (PD), it has been increasingly recognised that pathway-based polygenic risk approaches could provide an alternative strategy to identify a subset of PD cases that might be more prone to pathway-specific susceptibility. We hypothesised that lysosomal-based pathway approaches would identify novel genetic risk loci that could explain part of lysosomal-dependent neurodegeneration in PD. Methods A total of 7,668 patients with PD and 7,146 controls from 26 COURAGE-PD sites of European and East Asian ancestries were included. Lysosomal pathway-specific polygenic risk scores (LP-PRS) were generated using two complementary transfer strategies: a linkage-disequilibrium (LD)-adaptive approach using optimised clumping and thresholding parameters within validation cohorts, and a SNP-fixed approach directly transferring the optimised SNP set across cohorts. PRS associations were evaluated independently within each cohort and then combined in a meta-analysis. Single-cell RNA sequencing datasets (58 cases and 61 controls), including substantia nigra and midbrain tissues, were used to assess expression patterns of top LP-PRS-associated genes. Individuals within the top and bottom 10% of the LP-PRS distribution were classified as high-risk and low-risk, respectively. Clinical trajectories were assessed in three large cohorts with available clinical follow-up data. Results LP-PRS optimisation identified 49 independent SNPs spanning 35 lysosomal pathway genes, including 14 variants not previously reported in PD case-control GWAS meta-analyses. LP-PRS was significantly associated with increased PD risk across ancestries, with a pooled odds ratio (OR) estimate of 1.42 (95% CI=[1.36,1.47]) in the European cohorts and OR=1.15 (95% CI=[1.03,1.29]) in the East Asian cohorts, with minimal between-cohort heterogeneity. Single-cell RNA sequencing analyses revealed reproducible differential expression of several LP-PRS-associated genes across multiple brain regions and cell types, particularly oligodendrocytes and microglia. Longitudinal analyses over approximately 10 years identified four individuals within the high-risk LP-PRS control group who prospectively developed PD, highlighting the potential use of pathway-informed genetic stratification. Interpretation These findings support the contribution of common variants within lysosomal pathway genes to PD susceptibility across ancestries and further support a central role for endolysosomal biology in PD pathogenesis. This study also demonstrates the potential utility of biologically informed pathway-specific PRS approaches for genetic stratification in PD opening novel strategies for precision medicine in the future.