The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal

Abstract

Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genomewide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods:We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls).Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium between the variants.Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p=0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p=0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p=0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses of the pairwise LD revealed that E326K and rs35749011 are in very high LD (r 2 0.95). Conclusions:Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS studies of PD.

Coding variation in GBA explains the majority of the SYT11‐GBA Parkinson's disease GWAS locus

“…Further, we have shown that a previously reported GWAS signal at this locus can be largely explained by protein coding variability within GBA . These data are consistent with p.E365K being the functional effector allele underlying the original GWA locus (GBA‐SYT11 locus), as suggested previously . The results from this current study suggest that efforts directed at replacing or augmenting glucocerebrosidase activity already under way for PD may have wider‐ranging applicability than just for individuals with GD‐associated mutations in glucocerebrosidase.…”

Mutations in the SPTLC1 gene are a cause of juvenile amyotrophic lateral sclerosis that may be amenable to serine supplementation

“…For example, the identification of TREM2 mutations in a handful of patients diagnosed with Alzheimer's disease highlighted the role of microglia and inflammation in that form of neurodegenerative disease and paved the way for innovative approaches to therapy (33). The discovery of GBA mutations had a similar impact on Parkinson's disease research (34).…”

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

“…169,170 This might be because of a differential localization of α-syn pathology, primarily involving oligodendrocytes in MSA, as opposed to neurons in PD and DLB. Third, a number of GBA1 variants not associated with GD have been described in patients with PD 80,171,172 and DLB. 64 Finally, a substantial proportion of GBA1 mutations identified in DLB patients are "mild" variants rather than expected "severe" mutations.…”