GBA variation and susceptibility to multiple system atrophy

Anna I. Wernick, Ronald L. Walton, Shunsuke Koga, Alexandra I. Soto-Beasley, Michael G. Heckman, Ziv Gan-Or, Yingxue Ren, Rosa Rademakers, Ryan J. Uitti, Zbigniew K. Wszolek, William P. Cheshire, Dennis W. Dickson, Owen A. Ross

Research output: Contribution to journalArticlepeer-review


Introduction: Genetic variants in the glucocerebrosidase (GBA) gene have been previously associated with susceptibility to synucleinopathies. The risk is well-established in Lewy body disease but is not as confirmed for multiple system atrophy (MSA). We aim to evaluate associations between exonic variants in GBA and risk of neuropathologically-confirmed multiple system atrophy (MSA). Methods: Sanger gene sequencing of GBA was performed on 167 pathologically confirmed MSA patients collected at Mayo Clinic Florida Brain Bank, and data were extracted from whole-genome sequencing of 834 clinical controls. Common GBA variants were assessed for association with MSA. Rare GBA variants (and also all GBA variants) were collapsed together and evaluated for association with MSA risk using a gene-burden test. Results: A total of 17 exonic GBA variants were observed, including a novel p.Q112X variant that is likely pathogenic in a patient with mixed parkinsonism-cerebellar subtype MSA. The more common p.N409S and p.L483P variants that recessively cause Gaucher's disease (GD), and are associated with risk of Lewy body disease, were not observed. When collapsing across all GBA variants, the presence of any GBA variant was significantly more frequent in MSA patients than in controls (OR = 1.90, P = 0.031). However, this association was driven by p.T408M, which had a significantly higher frequency in MSA patients compared to controls (OR = 4.21, P = 0.002). There was no significant association with risk of MSA for the p.E365K variant (OR = 0.79, P = 0.72). Conclusions: Other than the specific GBA p.T408M variant, coding GBA variants are not associated with risk of MSA.

Original languageEnglish (US)
Pages (from-to)64-69
Number of pages6
JournalParkinsonism and Related Disorders
StatePublished - Aug 2020


  • GBA
  • Genetics
  • Multiple system atrophy

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology


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