Association of rare variants inARSAwith Parkinson’s disease

Abstract

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.

Identification of novel variants, genes and pathways potentially linked to Parkinson’s disease using machine learning

“…Additional selection criteria for UK Biobank and AMP PD were reported previously. 55,56 We performed the analysis on several groups of rare variants (allele frequency < 0.01): loss of function variants, nonsynonymous variants, potentially deleterious (CADD>20) variants and functional (including nonsynonymous, frame-shift, stop-gain, and splicing) variants.…”