Objective: To investigate the contribution of rare variants in lysosomal genes to Parkinson’s disease (PD) susceptibility.

Background: Variants in the lysosomal gene GBA1 are established risk factors for PD, but mounting evidence suggests that other genes involved in lysosomal metabolism (e.g., ASAH1, CTSB, GRN) may also influence PD risk. A broader genetic assessment of these underexplored lysosomal pathways is therefore needed to clarify their roles in PD pathogenesis.

Method: We analyzed a total of 8,632 PD patients and 70,654 controls, including 818 early-onset PD (EOPD) cases. First, we fully sequenced 36 lysosomal genes in 3,699 PD patients and 2,561 controls from four cohorts at McGill University. We then meta-analyzed our data with whole-exome and whole-genome sequencing from: (1) UK Biobank (2,970 PD patients and 65,000 controls) and (2) AMP-PD (1,963 PD patients and 3,093 controls). Using the SKAT-O, we evaluated associations between rare variants (minor allele frequency <1%) and PD in each gene. We conducted separate analyses for all rare variants, nonsynonymous variants, loss-of-function variants, and variants predicted to be deleterious (CADD score >20). Additionally, we performed per-domain analyses, focusing on protein regions encoding functional domains, as well as analyses in the EOPD cohort. Bonferroni correction for the number of genes was applied to all tests.

Results: A meta-analysis across all cohorts revealed a significant association between ST3GAL3 rare variants (p=0.0002) and PD. We also observed multiple nominally significant associations (p<0.05) in HGSNAT, ASAH1, CTSD, ST3GAL4, HEXA, and SGPP1.

Per-domain analyses identified a robust association for nonsynonymous variants in the HEXA β-acetyl hexosaminidase–like domain (p=0.0008). We observed nominal associations (p<0.05) for different domains in HGSNAT, ASAH1, CERK and GRN. Further domain-level analyses in EOPD samples showed an association with high CADD score variants in NAGLU (p=7.88E-8) and ST3GAL5 (p=0.005). The association in NAGLU was driven by the p.Ser141Thr variant, which was presented in 8 EOPD cases and 1 control of either Jewish or African/African-American ancestry.

Conclusion: Our findings indicate that rare variants in several lysosomal genes, beyond GBA1, may contribute to PD risk. This study reinforces the role of previously nominated genes (ASAH1, GRN) and identifies new associations, underscoring the importance of lysosomal pathways in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-rare-lysosomal-gene-variants-on-parkinsons-disease/