Category: Parkinson's Disease: Genetics
Objective: Assess the entire GBA1 gene in Parkinson’s disease from a single large population.
Background: The commonest genetic risk factor for Parkinson’s disease known to date is a variant in the GBA1 gene. Distribution of GBA1 variants varies across populations. Rarely the entire GBA1 gene has been studied in a large cohort from a single population.
Method: The GBA1 gene was assessed in 3402 Dutch Parkinson’s disease patients using next generation sequencing. Gene variant frequencies were compared to Dutch controls(n=655). Family history of Parkinson’s disease was compared in carriers of the most common variants and non-carriers.
Results: 15.0% of patients had a GBA1 non-synonymous variant, compared to 6.4% of controls (OR 2.6;p<0.001). 18 novel variants were detected. Variants previously associated with Gaucher’s disease were identified in 5.0% of patients compared to 1.5% of controls (OR 3.4;p<0.001). The rarely reported complex allele p.D140H+p.E326K appears to be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR 2.7;p=0.012). [Figure 1] shows a heat map of the descent of grandparents of these carriers. Visual inspection suggests the northern Netherlands as a possible founder location for this complex allele. Based on family histories of 417 patients (302 with a GBA1 variant and 115 without), the number of first-degree relatives with Parkinson’s disease was elevated among carriers (3.6%) as compared to non-carriers (2.0%) (OR 1.8;p=0.043). This was higher in p.D140H+p.E326K carriers (5.6%, 21/376) compared to p.E326K carriers (2.9%, 29/1014) (OR 2.0;p=0.022), indicative of a ‘dose-effect’ for different GBA1 variants [Figure 2].
Conclusion: Dutch Parkinson’s disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting for a large part of the mild p.E326K variant and the more severe Dutch p.D140H+p.E326K founder allele.
To cite this abstract in AMA style:
J. den Heijer, V. Cullen, M. Quadri, A. Schmitz, D. Hilt, P. Lansbury, H. Berendse, W. de Berg, R. de Bie, J. Boertien, A. Boon, M. Contarino, J. van Hilten, J. Hoff, T. van Mierlo, A. Munts, A. der Plas, M. Ponsen, F. Baas, D. Majoor-Krakauer, V. Bonifati, T. van Laar, G.J Groeneveld. A large-scale full GBA1 gene screening in Parkinson’s disease in the Netherlands: 18 novel and 1 ‘Dutch’ variant [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/a-large-scale-full-gba1-gene-screening-in-parkinsons-disease-in-the-netherlands-18-novel-and-1-dutch-variant/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2020
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-large-scale-full-gba1-gene-screening-in-parkinsons-disease-in-the-netherlands-18-novel-and-1-dutch-variant/