Anna I Wernick1, Ronald L Walton2, Shunsuke Koga2, Alexandra I Soto-Beasley2, Michael G Heckman3, Ziv Gan-Or4, Yingxue Ren5, Rosa Rademakers2, Ryan J Uitti6, Zbigniew K Wszolek6, William P Cheshire6, Dennis W Dickson2, Owen A Ross7. 1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, Greater, Manchester, UK. 2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. 3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA. 4. Department of Human Genetics, Department of Neurology and Neurosurgery, Neurological Institute, McGill University, Montréal, QC, Canada. 5. Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA. 6. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. 7. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Track, Mayo Graduate School, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: ross.owen@mayo.edu.
Abstract
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.
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 GBAp.T408M variant, coding GBA variants are not associated with risk of MSA.