Objective: The main objective of this study is to examine the burden of variants in genes that are known or suspected to be involved in PD in GBA-associated PD, as potential modifiers of risk among these patients.

Background: GBA variants are among the most common genetic risk factors associated with Parkinson’s disease (PD), present in up to 20% of patients with PD in different populations. The majority of GBA variant carriers do not develop PD, and there is a large heterogeneity in its clinical presentation. It is therefore clear that other factors, genetic and/or environmental, affect the development of GBA-associated PD.

Method: We compared the frequency of rare (minor allele frequency < 0.01) variants in 42 genes that are known or suspected to be involved in PD between 309 PD patients carrying a GBA variant (GBA-PD) and 2074 PD patients without GBA variants. Burden and optimized sequence Kernel association tests (SKAT-O) have been performed for each of the 42 genes.

Results: After Bonferroni correction for multiple testing, no significant association between GBA-PD and variants in the tested genes was observed. However, a nominally significant burden of GAK variants (p=0.00054) was found in the burden analysis of variants predicted to be pathogenic by Combined Annotation Dependent Depletion (CADD) score. One GAK nonsynonymous variant with a higher frequency in the GBA-PD group was located in a tensin phosphatase domain.

Conclusion: Based on these results, there is no strong evidence for burden of variants in PD-associated genes among GBA variant carriers. The nominally significant results suggest that larger studies are required to determine the potential role of these variants in GBA-PD

References: 1. Gan-Or Z, Amshalom I, Kilarski LL, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 2015;84(9):880-887. 2. Alcalay RN, Levy OA, Waters CC, et al. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 2015;138(Pt 9):2648-2658. 3. Gan-Or Z, Giladi N, Rozovski U, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 2008;70(24):2277-2283.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/burden-of-variants-in-parkinsons-disease-associated-genes-in-gba-mutation-carriers/