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

Neurosci Lett. 2017 Sep 29;658:48-52. doi: 10.1016/j.neulet.2017.08.040. Epub 2017 Aug 19.


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, genome-wide 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 (LD) 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 revealed that E326K and rs35749011 are in very high LD (r2 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 of PD.

Keywords: E326K; GWAS; Glucocerebrosidase; Parkinson’s disease; Synaptotagmin 11; T369M.

MeSH terms

  • Adult
  • Aged
  • Cohort Studies
  • Female
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study / methods
  • Genotype
  • Glucosylceramidase / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Parkinson Disease / genetics*
  • Polymorphism, Single Nucleotide / genetics*


  • Glucosylceramidase