Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease |
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| Authors: | Jennifer A Ruskey Lior Greenbaum Léanne Roncière Armaghan Alam Dan Spiegelman Christopher Liong Oren A Levy Cheryl Waters Stanley Fahn Karen S Marder Wendy Chung Gilad Yahalom Simon Israeli-Korn Vered Livneh Tsvia Fay-Karmon Roy N Alcalay Sharon Hassin-Baer Ziv Gan-Or |
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| Institution: | 1. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada;2. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada;3. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel;4. The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel;5. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;6. Faculty of Medicine, McGill University, Montréal, Quebec, Canada;7. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA;8. Taub Institute for Research on Alzheimer''s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA;9. Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA;10. Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel;11. Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel;12. Department of Human Genetics, McGill University, Montréal, Quebec, Canada |
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| Abstract: | BackgroundVariants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.MethodsGBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n?=?3044) from the Inflammatory Bowel Disease Exome Portal was used.ResultsFull GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR?=?2.7, 95%CI?=?1.9–3.8, p?<?0.0001).ConclusionWithout full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials. |
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| Keywords: | Corresponding author Montreal Neurological Institute and hospital The Department of Neurology & Neurosurgery The Department of Human Genetics McGill University 1033 Pine Avenue West Ludmer Pavilion room 312 Montreal QC H3A 1A1 Canada |
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