Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Eur J Med Genet. 2019 Jan;62(1):65-69. doi: 10.1016/j.ejmg.2018.05.005. Epub 2018 May 26.


Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.

Methods: GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used.

Results: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001).

Conclusion: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

MeSH terms

  • Adult
  • Aged
  • Female
  • Genetic Carrier Screening / methods
  • Genetic Carrier Screening / standards*
  • Genome-Wide Association Study / standards
  • Glucosylceramidase / genetics*
  • Heterozygote
  • Humans
  • Jews / genetics*
  • Male
  • Middle Aged
  • Parkinson Disease / genetics*
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis, DNA / standards


  • Glucosylceramidase