Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA , which encodes for the enzyme arylsulfatase A, remains controversial.
Objectives: To evaluate the association between rare ARSA variants and PD.
Methods: To study possible association of rare variants (minor allele frequency<0.01) in ARSA with PD, we performed burden analyses in six independent cohorts with a total of 5,801 PD patients and 20,475 controls, using optimized sequence Kernel association test (SKAT-O), followed by a meta-analysis.
Results: We found evidence for an association between functional ARSA variants and PD in four independent cohorts (P≤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 UKBB cohort (P=0.005) and in the meta-analysis (P=0.049). However, despite replicating in four independent cohorts, these results should be interpreted with caution as no association survived correction for multiple comparisons. Additionally, we describe two families with potential co-segregation of the ARSA variant p.E384K and PD.
Conclusions: Rare functional and loss-of-function ARSA variants may be associated with PD. Further replication in large case-control cohorts and in familial studies is required to confirm these associations.