Association of Rare Variants in ARSA with Parkinson's Disease

BackgroundSeveral lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear. ObjectivesTo study rare ARSA variants in PD. MethodsTo study rare ARSA variants (minor allele frequency < 0.01) in PD, we performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by a meta-analysis. ResultsWe found evidence for associations between functional ARSA variants and PD in four cohorts (P & LE; 0.05 in each) and in the meta-analysis (P = 0.042). We also found an association between loss-of-function variants and PD in the United Kingdom Biobank cohort (P = 0.005) and in the meta-analysis (P = 0.049). These results should be interpreted with caution as no association survived multiple comparisons correction. Additionally, we describe two families with potential co-segregation of ARSA p.E382K and PD. ConclusionsRare functional and loss-of-function ARSA variants may be associated with PD. Further replications in large case-control/familial cohorts are required. & COPY; 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.