Association of rare variants inARSAwith Parkinson’s disease

Abstract

AbstractBackgroundSeveral lysosomal genes are associated with Parkinson’s disease (PD), yet the association between PD andARSA, which encodes for the enzyme arylsulfatase A, remains controversial.ObjectivesTo evaluate the association between rareARSAvariants and PD.MethodsTo study possible association of rare variants (minor allele frequency<0.01) inARSAwith 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.ResultsWe found evidence for an association between functionalARSAvariants 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 theARSAvariant p.E384K and PD.ConclusionsRare functional and loss-of-functionARSAvariants may be associated with PD. Further replication in large case-control cohorts and in familial studies is required to confirm these associations.