Session Information
Date: Monday, September 23, 2019
Session Title: Genetics
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: To evaluate the frequency of GBA p.Glu326Lys (E326K) carriers in a large cohort of Parkinson’s disease patients of Ashkenazi Jewish origin (AJPD) and to estimate its risk for disease development and effect on severity.
Background: GBA is a major gene involved in PD. Carriers of different variants have a higher risk to develop PD. These variants include severe and mild alleles defined according to their effect on disease phenotype, all studied in association with PD, however E326K homozygotes do not have Gaucher disease.
Method: The GBA E326K variation was genotyped in 1200 AJPD that were also genotyped for other Ashkenazi founder GBA mutations (N370S, R496H, L444P, 84GG, IVS2+1G->A, V394L), the LRRK2 G2019S mutation, and the SMPD1 L302P mutation, and in 600 AJ controls. A specific TaqMan assay was designed to avoid artifact results due to the GBA pseudogene. Carriers’ status was confirmed by Sanger sequencing.
Results: 27 AJPD carried E326K (2.25%) compared to 4 among the 600 controls (0.6%, p-value for association 0.0126, Fisher’s exact test, OR=3.43, 95% CI 1.19-9.85, p=0.022). Since E326K frequency among the 600 controls was not statistically different from the frequency reported in gnomAD AJ non-neuro controls (Genome Aggregation Database, Lek et al., Nature 2016), we combined the two control groups and reevaluate the risk, comparing patients to 3829 controls (43 carriers). The OR for heterozygosity was 2.03 (95% CI: 1.25-3.29, p=0.0044). Of the 27 carriers 37% carried another known mutation (3 were compound heterozygotes, 5 carried the LRRK2 G2019S mutation, 1 was compound heterozygote and G2019S carrier, and 1 carried SMPD1 p.L302P mutation). AAO analysis demonstrated no difference between PD patients carrying only the E326K and non-carrier PD patients (17 and 784 patients, 61.0±8.96 and 61.6±11.05 years, respectively, p=0.82, t-test).
Conclusion: The GBA E326K variant doubles the risk to develop PD. However, many of the carriers also carry another known mutation in GBA, LRRK2 or SMPD1. When analyzing carriers of E326K only, there is no effect on the AAO compare to other non-carriers PD, therefore, the risk of E326K-only carriers should be reevaluated in comparison to a large cohort of AJ controls with a full mutation’s data.
To cite this abstract in AMA style:
O. Goldstein, M. Gana- Weisz, D. Cohen-Avinoam, A. Bar-Shira, A. Thaler, T. Shiner, A. Mirelman, N. Giladi, A. Orr-Urtreger. GBA p.Glu326Lys substitution increases the risk to develop Parkinson’s disease; is it enough to affect disease phenotype? [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/gba-p-glu326lys-substitution-increases-the-risk-to-develop-parkinsons-disease-is-it-enough-to-affect-disease-phenotype/. Accessed June 14, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-p-glu326lys-substitution-increases-the-risk-to-develop-parkinsons-disease-is-it-enough-to-affect-disease-phenotype/