Are rare heterozygous SYNJ1 variants associated with Parkinson's disease?

Konstantin Senkevich; Sitki Cem Parlar; Cloe Chantereault; Eric Yu; Jamil Ahmad; Jennifer A Ruskey; Farnaz Asayesh; Dan Spiegelman; Cheryl Waters; Oury Monchi; Yves Dauvilliers; Nicolas Dupré; Irina Miliukhina; Alla Timofeeva; Anton Emelyanov; Sofya Pchelina; Lior Greenbaum; Sharon Hassin-Baer; Roy N Alcalay; Ziv Gan-Or

doi:10.1101/2024.05.29.24307986

Are rare heterozygous SYNJ1 variants associated with Parkinson's disease?

medRxiv [Preprint]. 2024 Jun 1:2024.05.29.24307986. doi: 10.1101/2024.05.29.24307986.

Authors

Konstantin Senkevich^{1

2

3}, Sitki Cem Parlar^{1

3}, Cloe Chantereault^{1

3}, Eric Yu^{1

3}, Jamil Ahmad^{1

2}, Jennifer A Ruskey^{1

2}, Farnaz Asayesh^{1

3}, Dan Spiegelman¹, Cheryl Waters⁴, Oury Monchi^{2

5

6}, Yves Dauvilliers⁷, Nicolas Dupré^{8

9}, Irina Miliukhina¹⁰, Alla Timofeeva¹¹, Anton Emelyanov¹¹, Sofya Pchelina¹¹, Lior Greenbaum^{12

13

14}, Sharon Hassin-Baer^{12

14

15}, Roy N Alcalay^{4

12

16}, Ziv Gan-Or^{1

2

3}

Affiliations

¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada.
² Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada, Canada.
³ Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁴ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, NY, USA.
⁵ Département de radiologie, radio-oncologie et médecine nucléaire, Université de Montréal, Montréal, QC, Canada.
⁶ Centre de recherche de l'Institut universitaire de gériatrie de Montréal, Montréal, QC, Canada.
⁷ National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Guide-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France.
⁸ Neuroscience axis, CHU de Québec-Université Laval, Québec, QC, Canada.
⁹ Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
¹⁰ Institute of the Human Brain of RAS, St. Petersburg, Russia.
¹¹ First Pavlov State Medical University of St. Petersburg, Saint-Petersburg, Russia.
¹² Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹³ The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
¹⁴ The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.
¹⁵ The Movement Disorders Institute, Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel.
¹⁶ Division of Movement Disorders, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Abstract

Previous studies have suggested that rare biallelic SYNJ1 mutations may cause autosomal recessive parkinsonism and Parkinson's disease (PD). Our study explored the impact of rare SYNJ1 variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (P_fdr=0.040). Additionally, a meta-analysis focusing on patients with EOPD demonstrated an association between all rare SYNJ1 variants and PD (P_fdr=0.029). Rare SYNJ1 variants may be associated with sporadic PD, and more specifically with EOPD.

Keywords: Early-onset Parkinson’s disease; Parkinson’s disease; SYNJ1; genetics; rare variants.

Publication types

Preprint

Abstract

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