Revisiting the non-Gaucher-GBA-E326K carrier state: Is it sufficient to increase Parkinson's disease risk?

Orly Goldstein, Mali Gana-Weisz, Danielle Cohen-Avinoam, Tamara Shiner, Avner Thaler, Jesse M. Cedarbaum, Sally John, Maria Lalioti, Tanya Gurevich, Anat Bar-Shira, Anat Mirelman, Nir Giladi, Avi Orr-Urtreger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. Methods: 1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. Results: All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86–12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). Conclusions: Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.

Original languageEnglish
Pages (from-to)470-475
Number of pages6
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - Dec 2019


FundersFunder number
AbbVie Israel, Neuroderm Ltd.
Chaya Charitable Fund and Biogen
European Union 7th Framework Program
European Union 7th Framework Program and the Israel Science Foundation
Intec Pharma
Israeli Innovation Authority
Neuroderm Ltd. and Allergan
Phonetica Ltd.
Sagol School of Neuroscience
Teva NNE
Michael J. Fox Foundation for Parkinson's Research
National Parkinson Foundation
Esther B. Kahn Charitable Foundation
International Parkinson and Movement Disorder Society
Parkinson's Foundation
Sanofi Genzyme
Israel Science Foundation


    • GBA
    • Heterozygous mutation carrier
    • LRRK2
    • Oligogenic
    • Parkinson's disease


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