TY - JOUR
T1 - GBA variation and susceptibility to multiple system atrophy
AU - Wernick, Anna I.
AU - Walton, Ronald L.
AU - Koga, Shunsuke
AU - Soto-Beasley, Alexandra I.
AU - Heckman, Michael G.
AU - Gan-Or, Ziv
AU - Ren, Yingxue
AU - Rademakers, Rosa
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Cheshire, William P.
AU - Dickson, Dennis W.
AU - Ross, Owen A.
N1 - Funding Information:
Owen A. Ross: received support from R01-NS078086 , P50-NS072187 , U54 NS110435 and U54 NS100693 , The Little Family Foundation , and the Michael J. Fox Foundation . O.A.R. is an editorial board member of American Journal of Neurodegenerative Disease and Molecular Neurodegeneration.
Funding Information:
Owen A. Ross: received support from R01-NS078086, P50-NS072187, U54 NS110435 and U54 NS100693, The Little Family Foundation, and the Michael J. Fox Foundation. O.A.R. is an editorial board member of American Journal of Neurodegenerative Disease and Molecular Neurodegeneration.We would like to thank all those who have contributed to our research, particularly the patients and families who donated brain and DNA samples for this work. We are grateful to all patients, family members, and caregivers who agreed to brain donation; without their donation these studies would have been impossible. We also acknowledge expert technical assistance of Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry. This project was supported by the Mayo Clinic Center for Individualized Medicine. Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence and a Lewy body dementia Center WithOut Walls (NINDS U54 NS110435). OAR is supported in part by the Michael J. Fox Foundation, US Department of Defense (W81XWH-17-1-0249), the Mayo Clinic LBD Functional Genomics Program and The Little Family Foundation. Samples included in this study were clinical controls or brain donors to the brain bank at Mayo Clinic in Jacksonville which is supported by Mayo Clinic Foundation, the Mayo Clinic Center for Individualized Medicine, CurePSP and the Tau Consortium. SK is supported by a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
We would like to thank all those who have contributed to our research, particularly the patients and families who donated brain and DNA samples for this work. We are grateful to all patients, family members, and caregivers who agreed to brain donation; without their donation these studies would have been impossible. We also acknowledge expert technical assistance of Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry. This project was supported by the Mayo Clinic Center for Individualized Medicine . Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence and a Lewy body dementia Center WithOut Walls (NINDS U54 NS110435). OAR is supported in part by the Michael J. Fox Foundation , US Department of Defense ( W81XWH-17-1-0249 ), the Mayo Clinic LBD Functional Genomics Program and The Little Family Foundation . Samples included in this study were clinical controls or brain donors to the brain bank at Mayo Clinic in Jacksonville which is supported by Mayo Clinic Foundation , the Mayo Clinic Center for Individualized Medicine , CurePSP and the Tau Consortium . SK is supported by a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
Ziv Gan-Or: Receives research support from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canadian Glycomics Network (GlycoNet), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program, the Fonds de recherche du Québec - Santé (FRQS) and Parkinson Canada. He is an Associate Editor in the Journal of Parkinson’s Disease and a member of the editorial board of Parkinsonism and Related Disorders. ZGO is consulting for Lysosomal Therapeutics Inc., Denali, Prevail Therapeutics, Idorsia and Inception Sciences (Ventus).
Funding Information:
Zbigniew K. Wszolek: receives research support from P50-NS072187, NIH/NIA (primary) and NIH/NINDS (secondary) 1U01AG045390-01A1, Mayo Clinic Center for Regenerative Medicine, the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa, the Haworth Family Professorship in Neurodegenerative Diseases fund, and by the Albertson Parkinson's Research Foundation. He serves as co-editor-in-chief of Neurologia i Neurochirurgia Polska and is on the editorial boards of European Journal of Clinical and Experimental Medicine, Clinical and Experimental Medical Letters, and Wiadomosci Lekarskie; holds and has contractual rights for receipt of future royalty payments from patents for “A Novel Polynucleotide Involved in Heritable Parkinson’s Disease”; and received royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2016, 2017) and the European Journal of Neurology (Wiley Blackwell, 2016, 2017). He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as Co-PI of the Mayo Clinic APDA Center for Advanced Research.
Funding Information:
Dennis W. Dickson: receives support from P50-AG016574, P50-NS072187, P01-AG003949, and CurePSP: Foundation for PSP | CBD and Related Disorders. D.W.D. is an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology and is editor in chief of American Journal of Neurodegenerative Disease and International Journal of Clinical and Experimental Pathology.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
KW - GBA
KW - Genetics
KW - Multiple system atrophy
UR - http://www.scopus.com/inward/record.url?scp=85087291691&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087291691&partnerID=8YFLogxK
U2 - 10.1016/j.parkreldis.2020.06.007
DO - 10.1016/j.parkreldis.2020.06.007
M3 - Article
C2 - 32623306
AN - SCOPUS:85087291691
SN - 1353-8020
VL - 77
SP - 64
EP - 69
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
ER -