Association of Rare Variants in ARSA with Parkinson's Disease

Konstantin Senkevich, Mariia Beletskaia, Aliza Dworkind, Eric Yu, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Lior Greenbaum, Sharon Hassin-Baer, Ilya Nagornov, Alexandr Tyurin, Irina Miliukhina, Alla Timofeeva, Anton EmelyanovJean François Trempe, Ekaterina Zakharova, Roy N. Alcalay, Sofya Pchelina, Ziv Gan-Or*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear. Objectives: To study rare ARSA variants in PD. Methods: To 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. Results: We found evidence for associations between functional ARSA variants and PD in four 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 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. Conclusions: Rare functional and loss-of-function ARSA variants may be associated with PD. Further replications in large case–control/familial cohorts are required.

Original languageEnglish
Pages (from-to)1806-1812
Number of pages7
JournalMovement Disorders
Volume38
Issue number10
DOIs
StatePublished - Oct 2023

Funding

FundersFunder number
Silverstein Foundation
Michael J. Fox Foundation for Parkinson's Research
Parkinson's Foundation

    Keywords

    • ARSA
    • Parkinson's disease
    • lysosomal genes
    • rare variants

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