Regular ArticleRevisiting the non-Gaucher-GBA-E326K carrier state: Is it sufficient to increase Parkinson's disease risk?
Introduction
The GBA gene (HGNC 4177) encodes the lysosomal enzyme glucocerebrosidase (GCase) that catalyzes the hydrolysis of glucosylceramide into free ceramide and glucose, within the lysosomal compartment. Mutations in this gene cause the recessive Gaucher's disease (GD). In the past two decades, studies unequivocally established the association of GBA heterozygosity to Parkinson's disease (PD) [1]; recently reviewed in [2,3]. Heterozygous carriers of GBA mutations have an increased frequency of PD, and 7%–10% of sporadic PD patients belong to this group of GBA-carriers. In the Ashkenazi Jewish (AJ) population, about 19% of PD patients carry GBA-founder-mutations [4,5]. This high percentage is mostly due to the relatively homogenous genetic architecture of the AJ population, a result of many generations maintaining relatively closed communities, with minimal intermarriage with other ethnic groups. It is due to long regions of linkage disequilibrium (LD) and blocks of shared haplotypes, that these variants are more common in this population compared to others, and easier to identify. This unique population allows researchers to better understand the correlation and effect of each variant to disease risk and phenotype, in a relatively small cohort size. Indeed, a differential effect on PD phenotype was already observed in this population, and confirmed in world-wide cohorts showing significantly higher odds ratio and lower age-at-disease-onset for carriers of severe mutations (that cause type 2 and 3 neuropathic GD), compared to carriers of mild mutations (that cause GD type 1, non-neuropathic) [4].
Recently, two mutations in GBA, E326K and T369 M that are not known to cause GD in homozygotes, were evaluated in a cohort of 6249 PD patients and 6032 European controls, demonstrating significantly elevated risk for PD (OR: 2.04 and 1.53, respectively [6]. For E326K carriers, Ruskey et al. [7] recently showed an OR of 5.5 in a cohort of 735 Ashkenazi PD patients. Since E326K is a frequent variant among Europeans, Finnish and AJ (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to assess its association with PD. We evaluate here the founder GBA mutations in the largest AJ- PD cohort of 1200 consecutively recruited patients, and suggest that E326K and T369M form a separate group of PD-associated-GBA variants, with different patterns of effects on disease risk and age-at-onset in carriers, compared to those who carry mild or severe mutations.
Section snippets
Population
Twelve hundreds unrelated PD patients of full AJ origin were consecutively recruited. They were examined at the Movement Disorders Unit at the Tel Aviv Sourasky Medical Center between 2005 and 2016. Information regarding the recruitment, diagnosis, and sample collections were previously described [4,5,8,9]. These references include the genotypes of the first 995 and 651 recruited patients for 7 GBA mutations (N370S, R496H, L444P, 84GG, IVS2 + 1G- > A, V394 L, Rec370) and LRRK2-G2019S, and the
Genotypes and alleles frequencies in PD patients
Of the 1200 AJ-PD, 215 carried only one GBA mutation (17.9%), 145 carried the LRRK2-G2019S mutation only (12.1%), and 8 carried the SMPD1-L302P mutation only (0.7%, Fig. 1). Twenty PD patients carried two mutations in GBA (1.7%, 4 of them homozygotes N370S), 24 carried mutations in GBA and LRRK2 (2.0%), and 1 carried a mutation in the GBA gene and a mutation in the SMPD1 gene. Sixty-six percent (787 patients) did not carry a mutation in any of the variants tested. Of the 215 PD patients who
Discussion
In the past year, strong evidence associated E326K and T369M variants to increased risk in PD [6]. These variants are not known to cause GD, and as such, were considered polymorphic changes for many years. The observation that variants in GBA are associated with PD and not with GD emphasizes the complexity of GBA-PD relationship, and highlights the need for a better understanding of the mechanisms in which these variants contribute to PD.
Due to the additional screening of E326K, T369M and R44C
Funding
This work was supported by Michael J Fox Foundation, and Kahn Foundation.
Declaration of competing interest
Orly Goldstein, Mali Gana-Weisz, Danielle Cohen-Avinoam, Tamara Shiner, Anat Bar-Shira, and Anat Mirelman have no conflict of interest. Avner Thaler reports receiving honorary from ABBVIE. Maria Lalioti and Sally John are employees of Biogen. Jesse M. Cedarbaum is a former employee of and shareholder in Biogen. Tanya Gurevich reports advisory board membership with honoraria to her and to her Institution from AbbVie Israel, Neuroderm Ltd. and Allergan, research support from Phonetica Ltd.,
Acknowledgements
The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about.
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The GBA-370Rec Parkinson's disease risk haplotype harbors a potentially pathogenic variant in the mitochondrial gene SLC25A44
2021, Molecular Genetics and MetabolismCitation Excerpt :Since GBAP1-rs550074330 was detected only in N370S carriers, and was not detected on any chromosome that did not carry the N370S mutation, we suggest that it had probably occurred on a chromosome already carrying the GBA-N370S mutation, creating a new allele with an additional missense mutation in the adjacent SLC25A44 gene (p.Met27Val, CADD score 20.9). The OR for PD among AJ-rs550074330 carriers is 2.33, showing a trend toward significance (p = 0.069), and it is more similar to the OR in N370S carriers (OR = 2.78) than previously published for 370Rec (ORs 15.3 and 12.8, refs [2, 11], respectively). To date, the small number of PD patients carrying the 370Rec haplotype, however, is too small to determine if this allele confers a unique clinical PD phenotype.
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