Rare-variant burden across lysosomal genes implicates sialylation and ganglioside metabolism in Parkinson’s disease

Lysosomal dysfunction is central to Parkinson's disease pathogenesis, with <i>GBA1</i> as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinson's disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding <i>GBA1</i>) in 8,267 individuals with Parkinson's disease and 68,208 controls, including a subset of 793 early-onset Parkinson's disease (≤50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3,456 Parkinson's disease patients and 2,664 controls) and results were combined with whole-genome sequencing data from the UK Biobank (2,848 cases, 62,451 controls), and from the Accelerating Medicines Partnership - Parkinson's Disease (1,963 cases, 3,093 controls). We analysed the association of rare variants in these genes with Parkinson's disease using Sequence Kernel Association Test-Optimal (SKAT-O) across variant classes (all rare variants, nonsynonymous, loss-of-function and predicted damaging variants with a Combined Annotation Dependent Depletion (CADD) score >20), with meta-analysis across cohorts. We additionally performed per-domain analyses for variants in gene segments encoding functional domains. False discovery rate correction was applied. Meta-analysis identified a significant association between rare variants in <i>ST3GAL3</i> and Parkinson's disease (Pfdr=0.04). Several additional lysosomal genes showed nominal associations (P<0.05), including <i>HGSNAT, ASAH1, CTSD, HEXA, ST3GAL4</i> and <i>SGPP1</i>. Domain-based analyses identified a strong enrichment of nonsynonymous variants within the beta-acetyl-hexosaminidase-like domain of HEXA (P = 8.0 × 10), although this signal did not survive correction for multiple testing (Pfdr=0.154). In early-onset Parkinson's disease, domain-based analyses revealed significant associations in <i>NAGLU</i> (Pfdr=7.3×10) and <i>ST3GAL5</i> (Pfdr=0.03). Together, these results provide genetic evidence that rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to Parkinson's disease susceptibility beyond <i>GBA1</i>, highlighting biologically coherent pathways for future replication and functional investigation.