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 Emelyanov; Jean François Trempe; Ekaterina Zakharova; Roy N. Alcalay; Sofya Pchelina; Ziv Gan-Or

doi:10.1002/mds.29521

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

Neurology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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 language	English
Pages (from-to)	1806-1812
Number of pages	7
Journal	Movement Disorders
Volume	38
Issue number	10
DOIs	https://doi.org/10.1002/mds.29521
State	Published - Oct 2023

Keywords

ARSA
Parkinson's disease
lysosomal genes
rare variants

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10.1002/mds.29521

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Senkevich, K., Beletskaia, M., Dworkind, A., Yu, E., Ahmad, J., Ruskey, J. A., Asayesh, F., Spiegelman, D., Fahn, S., Waters, C., Monchi, O., Dauvilliers, Y., Dupré, N., Greenbaum, L., Hassin-Baer, S., Nagornov, I., Tyurin, A., Miliukhina, I., Timofeeva, A., ... Gan-Or, Z. (2023). Association of Rare Variants in ARSA with Parkinson's Disease. Movement Disorders, 38(10), 1806-1812. https://doi.org/10.1002/mds.29521

@article{d8b4e75b596a42aeae79038ddbbde60d,

title = "Association of Rare Variants in ARSA with Parkinson's Disease",

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.",

keywords = "ARSA, Parkinson's disease, lysosomal genes, rare variants",

author = "Konstantin Senkevich and Mariia Beletskaia and Aliza Dworkind and Eric Yu and Jamil Ahmad and Ruskey, {Jennifer A.} and Farnaz Asayesh and Dan Spiegelman and Stanley Fahn and Cheryl Waters and Oury Monchi and Yves Dauvilliers and Nicolas Dupr{\'e} and Lior Greenbaum and Sharon Hassin-Baer and Ilya Nagornov and Alexandr Tyurin and Irina Miliukhina and Alla Timofeeva and Anton Emelyanov and Trempe, {Jean Fran{\c c}ois} and Ekaterina Zakharova and Alcalay, {Roy N.} and Sofya Pchelina and Ziv Gan-Or",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2023",

month = oct,

doi = "10.1002/mds.29521",

language = "אנגלית",

volume = "38",

pages = "1806--1812",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley & Sons Inc.",

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Senkevich, K, Beletskaia, M, Dworkind, A, Yu, E, Ahmad, J, Ruskey, JA, Asayesh, F, Spiegelman, D, Fahn, S, Waters, C, Monchi, O, Dauvilliers, Y, Dupré, N, Greenbaum, L , Hassin-Baer, S, Nagornov, I, Tyurin, A, Miliukhina, I, Timofeeva, A, Emelyanov, A, Trempe, JF, Zakharova, E, Alcalay, RN, Pchelina, S & Gan-Or, Z 2023, 'Association of Rare Variants in ARSA with Parkinson's Disease', Movement Disorders, vol. 38, no. 10, pp. 1806-1812. https://doi.org/10.1002/mds.29521

TY - JOUR

T1 - Association of Rare Variants in ARSA with Parkinson's Disease

AU - Senkevich, Konstantin

AU - Beletskaia, Mariia

AU - Dworkind, Aliza

AU - Yu, Eric

AU - Ahmad, Jamil

AU - Ruskey, Jennifer A.

AU - Asayesh, Farnaz

AU - Spiegelman, Dan

AU - Fahn, Stanley

AU - Waters, Cheryl

AU - Monchi, Oury

AU - Dauvilliers, Yves

AU - Dupré, Nicolas

AU - Greenbaum, Lior

AU - Hassin-Baer, Sharon

AU - Nagornov, Ilya

AU - Tyurin, Alexandr

AU - Miliukhina, Irina

AU - Timofeeva, Alla

AU - Emelyanov, Anton

AU - Trempe, Jean François

AU - Zakharova, Ekaterina

AU - Alcalay, Roy N.

AU - Pchelina, Sofya

AU - Gan-Or, Ziv

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

KW - ARSA

KW - Parkinson's disease

KW - lysosomal genes

KW - rare variants

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U2 - 10.1002/mds.29521

DO - 10.1002/mds.29521

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SN - 0885-3185

VL - 38

SP - 1806

EP - 1812

JO - Movement Disorders

JF - Movement Disorders

IS - 10

ER -

Association of Rare Variants in ARSA with Parkinson's Disease

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