Jennifer A Ruskey1, Lior Greenbaum2, Léanne Roncière3, Armaghan Alam4, Dan Spiegelman1, Christopher Liong5, Oren A Levy6, Cheryl Waters5, Stanley Fahn5, Karen S Marder6, Wendy Chung7, Gilad Yahalom8, Simon Israeli-Korn9, Vered Livneh9, Tsvia Fay-Karmon9, Roy N Alcalay6, Sharon Hassin-Baer8, Ziv Gan-Or10. 1. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada. 2. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Faculty of Medicine, McGill University, Montréal, Quebec, Canada. 4. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. 5. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. 6. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; 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. 7. Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. 8. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel. 9. Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel. 10. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address: ziv.gan-or@mcgill.ca.
Abstract
BACKGROUND: Variants 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. METHODS: GBA 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. RESULTS: Full 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). CONCLUSION: Without 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.
BACKGROUND: Variants 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. METHODS:GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PDpatients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used. RESULTS: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PDpatients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PDpatients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PDpatients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001). CONCLUSION: Without 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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