Rare‐Variant Burden across Lysosomal Genes Implicates Sialylation and Ganglioside Metabolism in Parkinson's Disease

Abstract Background Lysosomal dysfunction is central to Parkinson's disease (PD) pathogenesis, with GBA1 representing the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid, and ceramide metabolism have been proposed as contributors to PD, highlighting the need for genetic analyses across these pathways. Objectives The aim was to evaluate the contribution of rare variants across lysosomal genes to PD risk. Methods We analyzed rare variants (minor allele frequency ≤0.01) across 36 lysosomal genes in 8267 individuals with PD and 68,208 controls, including 793 early‐onset PD (≤50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3456 cases and 2664 controls) and combined with whole‐genome sequencing data from the United Kingdom (UK) Biobank (2848 cases, 62,451 controls) and the Accelerating Medicines Partnership‐PD cohort (1963 cases, 3093 controls). Associations were tested using Sequence Kernel Association Test‐Optimal across variant classes (rare variants, nonsynonymous, loss‐of‐function, and predicted damaging variants with combined annotation‐dependent depletion score >20), followed by meta‐analysis across cohorts. Domain‐level analyses were performed for variants located within protein domains. False discovery rate (FDR) correction was applied. Results Meta‐analysis identified a significant association between rare variants in ST3GAL3 and Parkinson's disease (Pfdr = 0.04). Domain‐based analyses showed enrichment of nonsynonymous variants within the β‐acetyl‐hexosaminidase–like domain of HEXA ( P = 8.0 × 10 −4 ), although this signal did not survive correction (Pfdr = 0.154). In early‐onset PD, domain‐based analyses identified significant associations in NAGLU (Pfdr = 7.3 × 10 −6 ) and ST3GAL5 (Pfdr = 0.03). Conclusions Rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to PD susceptibility beyond GBA1 , highlighting pathways for future replication and investigation. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.