Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)65-69
Number of pages5
JournalEuropean Journal of Medical Genetics
Issue number1
StatePublished - Jan 2019


FundersFunder number
Canadian Consortium on Neurodegeneration in Aging
Helmsley IBD Exomes Program
National Institutes of HealthUL1TR000040
National Institute of Neurological Disorders and StrokeK02NS080915
National Center for Research ResourcesUL1RR024156
Michael J. Fox Foundation for Parkinson's Research
Brookdale Foundation
Parkinson's Foundation
Consortium canadien en neurodégénérescence associée au vieillissement


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