Large-scale assessment of polyglutamine repeat expansions in Parkinson disease
Abstract
Objectives:
We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD).
Methods:
We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations.
Results:
We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci.
Conclusions:
Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.
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Supplementary Material
AUTHOR AFFILIATIONS
From the Centre for Genetic Epidemiology (L.W., M.S.), Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany; Department of Neurology (J.O.A.), St. Olavs Hospital and NTNU, Trondheim, Norway; Institute of Molecular Bioimaging and Physiology (G.A.), National Research Council, Section of Catanzaro, Italy; Division of Molecular Biology and Human Genetics (S.B., J.C.), University of Stellenbosch, Cape Town, South Africa; General Hospital of Syros (M.B.); Hygeia Hospital (M.B.), Clinic of Neurodegenerative Disorders, Athens; 2nd Neurology Clinic (M.B., L.S.), University of Athens, Attikon Hospital, Greece; INSERM U 1127 (A.B., S.L.), CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Department of Neurology (S.J.C.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; School of Clinical and Experimental Medicine (C.C., K.E.M.), College of Medical and Dental Sciences, University of Birmingham and City Hospital, Birmingham, UK; Neurodegenerative Brain Diseases Group (D.C., J.T., C.V.B.), Department of Molecular Genetics, VIB, Antwerpen; Institute Born-Bunge (D.C., J.T., C.V.B.), University of Antwerp; Department of Neurology (D.C.), University Hospital Antwerpen, Belgium; Department of Neurology (A.D.), Max Planck Institute for Psychiatry, Munich; Helmholtz Zentrum München (G.E., P.L.), German Research Centre for Environmental Health (Gmbh), Neuherberg, Germany; Djavad Mowafhagian Centre for Brain (M.J.F.), University of British Columbia, Vancouver, Canada; Parkinson Institute (S.G.), Istituti Clinici di Perfezionamento, Milano, Italy; Cyclotron Research Centre (G.G.), Department of Neurology, University of Liège, Belgium; Department of Neurology (G.M.H., G.X.), Faculty of Medicine, University of Thessaly and Institute of Biomedical Research and Technology, CERETETH, Larissa, Greece; Center for Biomedicine (A.A.H., P.P.P.), EURAC Bolzano, Italy; Department of Neurology (N.H., H.T.), Juntendo University School of Medicine, Tokyo, Japan; Institute of Neurogenetics (C.K.), University of Luebeck, Germany; Department of Neurology (B.J., S.S.P.), Seoul National University Hospital; ILSONG Institute of Life Science (Y.J.K., K.-C.Y.), Hallym University, Hallym Institute of Translational Genomics & Bioinformatics, Department of Neurology, Hallym University Sacred Heart Hospital, Korea; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou and Chung-Shan Medical University Hospital, Taichung, Taiwan; The Dublin Neurological Institute at the Mater Misericordiae University Hospital (T.L.), and Conway Institute, University College Dublin, Ireland; Movement Disorders Centre (A.E.L.), Toronto Western Hospital, University of Toronto, Canada; Clinical Neurology Research Centre (V.M.), Department of Medicine & Therapeutics, The Chinese University of Hong Kong, 10/F, Clinical Sciences Building, Prince of Wales Hospital, Shatin, New Territories, Hong Kong; Department of Neurology (B.J.-M., G.O.), Medical University of Silesia, Katowice, Poland; Eskitis Institute for Cell and Molecular Therapies (G.D.M.), Griffith University, Australia; Neurosciences Department (K.E.M., J.D.S.), Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust; Department of Neurology (L.P., M.T.), Oslo University Hospital, Norway; Institute of Neurology (A.Q.), Department of Medical Sciences, University Magna Graecia, Catanzaro; Institute of Molecular Bioimaging and Physiology (A.Q.), National Research Council, Section of Catanzaro, Italy; Tanz Centre for Research in Neurodegenerative Diseases (E.R.), Department of Medicine, University of Toronto, Canada; Departments of Neuroscience (O.A.R.) and Neurology (R.J.U., Z.W.), Mayo Clinic, Jacksonville, FL; Divisions of Basic Neurosciences & Cell Biology (L.S.), Biomedical Research Foundation of Academy of Athens, Greece; University of Queensland Centre for Clinical Research (P.A.S.), Herston, Australia; Department of Neurology (E.K.T., Y.Z.), Singapore General Hospital, National Neuroscience Institute, and Duke NUS Graduate Medical School, Singapore; Department of Medical Epidemiology and Biostatistics (K.W.), Karolinska Institute, Stockholm, Sweden; Department of Neurodegenerative Diseases (T.G., R.K., M.S.), Hertie Institute for Clinical Brain Science Research, University of Tubingen, Germany; Department of Neurology (D.M.M.), North Shore University Health System, Evanston, IL; and Clinical and Experimental Neuroscience (R.K.), Luxembourg Centre for Systems Biomedicine, University of Luxembourg, and Centre Hospitalier de Luxembourg, Luxembourg.
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Information & Authors
Information
Published In
Copyright
© 2015 American Academy of Neurology.
Publication History
Received: October 8, 2014
Accepted: May 21, 2015
Published online: September 9, 2015
Published in issue: October 13, 2015
Disclosure
L. Wang reports no disclosures relevant to the manuscript. J. Aasly is supported by the Norwegian Research Council and Reberg's Legacy. G. Annesi, S. Bardien, M. Bozi, A. Brice, J. Carr, S. Chung, C. Clarke, D. Crosiers, A. Deutschländer, and G. Eckstein report no disclosures relevant to the manuscript. M. Farrer reports grants from the Canadian Federal Government, Cunhill Foundation, and BC Leading Edge Endowment, during the conduct of the study; also personal fees from Gentech and Teva, outside the submitted work; In addition, Dr. Farrer has a patent on genetic variability in LRRK2 and Parkinson disease (US8409809, US8455243B2) and on LRRK2 mouse models subsequently developed with royalties paid. S. Goldwurm, G. Garraux, G. Hadjigeorgiou, and A. Hicks report no disclosures relevant to the manuscript. N. Nobutaka Hattori has been serving as an advisory board member for Boehringer Ingelheim and as a result of attending advisory board meetings he received personal compensation. Nobutaka Hattori also has been serving as an advisory board member for FP Pharmaceutical Company and by attending these advisory meetings he received personal compensation. He has been consulting with Otsuka Pharmaceutical Company, Kyowa Hakko Kirin Pharmaceutical Company, GlaxoSmithKline, Novartis, and Schering-Plough, and when he attended these advisory board meetings, he received personal compensation. C. Klein reports no disclosures relevant to the manuscript. B. Jeon has received funding for travel from GlaxoSmithKline Korea and Novartis Korea, and has received research support as principal investigator from Novartis, Boehringer Ingelheim, Ipsen Korea, the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A030001), ABRC (Advanced Biometric Research Center), KOSEF (Korea Science and Engineering Foundation), Seoul National University Hospital, the Mr. Chung Suk-Gyoo and Sinyang Cultural Foundation, and the Song Foundation. Y. Kim, S. Lesage, and J. Lin report no disclosures relevant to the manuscript. T. Lynch has served on an advisory board for Biogen and Novartis and has received honoraria from Lundbeck, Biogen, and Boehringer Ingelheim. P. Lichtner reports no disclosures relevant to the manuscript. A. Lang has served as an advisor for Abbott, Allon Therapeutics, AstraZeneca, Biovail, Boehringer Ingelheim, Cephalon, Ceregene, Eisai, Medtronic, Lundbeck A/S, Novartis, Merck Serono, Solvay, and Teva, and received grants from Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, and Ontario Problem Gambling Research Centre and has served as an expert witness in cases related to the welding industry. V. Mok reports no disclosures relevant to the manuscript. B. Jasinska-Myga was partially supported by the Robert and Clarice Smith Fellowship Program and the Pacific Alzheimer Research Foundation grant C06-01. G. Mellick reports no disclosures relevant to the manuscript. K. Morrison serves on the editorial board of Neurodegenerative Disease Management and previously served on the editorial board of Journal of Neurology and Neuromuscular Disorders. She has received grant support from Parkinson's UK, The Medical Research Council UK, the Wellcome Trust, and the Midlands Neurological Teaching and Research Fund. G. Opala was partially supported by the Robert and Clarice Smith Fellowship Program and the Pacific Alzheimer Research Foundation grant C06-01. L. Pihlstrøm, P. Pramstaller, S. Park, A. Quattrone, and E. Rogaeva report no disclosures relevant to the manuscript. O. Ross serves on the editorial board of the American Journal of Neurodegenerative Disease, PLoS One, and Parkinsonism and Related Disorders journals. He is funded by NIH grant R01 NS078086 and the Mayo Clinic Udall Center of Excellence for Parkinson's Disease Research (P50 NS072187), and received research support from the Michael J. Fox Foundation. L. Stefanis has received a grant for genetic studies of PD from the Hellenic Secretariat of Research and Technology (PENED 2003), in which Novartis Hellas acted as a cosponsor. J. Stockton, P. Silburn, and J. Theuns report no disclosures relevant to the manuscript. E. Tan serves as an editor of Parkinsonism and Related Disorders, European Journal of Neurology, and Basal Ganglia, and is the chief editor of Annals Academy of Medicine. He is funded by the National Medical Research Council, Duke-NUS Graduate Medical School, and Singapore Millennium Foundation. He has received honoraria from Novartis, Boehringer Ingelheim, and GSK. M. Toft serves on the editorial board of PLoS One and is supported by research grants from the Research Council of Norway and South-Eastern Norway Regional Health Authority. H. Tomiyama received a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for Scientific Research (to H.T.: 21591098) and Grants-in-Aid from the Research Committee of CNS Degenerative Diseases and Perry syndrome (to HT: 22140901). C. Van Broeckhoven reports no disclosures relevant to the manuscript. R. Uitti, MD, has received research funding from the NIH, PARRF, PSG, Noscira, Inc., and Advanced Neuromodulation Systems, Inc. Dr. Uitti has served as a Continuing Medical Educator for the AAN. His institution has received annual royalties from the licensing of the technology related to PARK8/LRRK2 greater than the federal threshold for significant financial interest; Dr. Uitti has not received any royalties. Dr. Uitti receives an honorarium as associate editor of Neurology®. K. Wirdefeldt reports no disclosures relevant to the manuscript. Z. Wszolek serves as co–editor-in-chief of Parkinsonism and Related Disorders, associate editor of the European Journal of Neurology, and on the editorial boards of Neurologia i Neurochirurgia Polska, Advances in Rehabilitation, the Medical Journal of the Rzeszow University, and Clinical and Experimental Medical Letters. Dr. Wszolek holds and has contractual rights for receipt of future royalty payments from patents re: A novel polynucleotide involved in heritable Parkinson's disease; received royalties from publishing Parkinsonism and Related Disorders (Elsevier 2012, 2013, 2014) and the European Journal of Neurology (Wiley-Blackwell 2012, 2013, 2014); receives educational research support from Allergan, Inc., research support from NIH/NINDS P50NS072187, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF 90052031/PAU 90052). G. Ximerisiou, K. Yueh, and Y. Zhao report no disclosures relevant to the manuscript. T. Gasser serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society), and the European Union (MeFoPa, Mendelian Forms of Parkinsonism). He received speakers honoraria from Novartis, Merck Serono, Schwarz Pharma, Boehringer Ingelheim, and Valeant Pharma and royalties for his consulting activities from Cephalon Pharma and Merck Serono. Dr. Gasser holds a patent concerning the LRRK2 gene and neurodegenerative disorders. D. Maraganore has received research funding support from the NIH (R01-ES10751), the Michael J. Fox Foundation (LEAPS award, Edmond J. Safra Global Genetics Consortia award), Alnylam Pharmaceutical and Medtronic, Inc. (study of α-synuclein genotypes and outcomes in Parkinson disease), and GE Healthcare (imaging biomarker studies of delayed sequelae of mild traumatic brain injury). He is on the editorial board of Parkinsonism and Related Disorders. He has a patent filed for a method to treat Parkinson disease. It has been licensed to Alnylam Pharmaceuticals and he has received more than $10,000 in royalty payments. R. Krüger serves as editor of European Journal of Clinical Investigation, Journal of Neural Transmission, and Parkinsonism and Related Disorders and associate editor of BMC Neurology; has received research grants of the German Research Council (DFG; KR2119/8-1), the Michael J. Fox Foundation (USA), the Fritz Thyssen Foundation (Germany), and the Fond National de Recherche (Luxembourg), as well as speakers honoraria and/or travel grants from AbbVie, St. Jude, and Medtronic. M. Sharma received funding support from the Michael J. Fox Foundation USA and the EU-JPND program of neurodegenerative diseases. Dr. Sharma serves on the editorial board of the American Journal of Neurodegenerative Disease and PLoS One. Dr. Sharma reports no disclosures related to this study. Go to Neurology.org for full disclosures.
Study Funding
The samples were obtained from the Parkinson Institute Biobank (http://www.parkinsonbiobank.com), member of the Telethon Network of Genetic Biobank (project GTB12001) funded by TELETHON Italy, and supported by Fondazione Grigioni per il Morbo di Parkinson.
Authors
Author Contributions
Lisa Wang, MSc: Ms. Wang performed statistical analysis and wrote the draft. Jan O. Aasly, MD: Dr. Aasly contributed samples and collected phenotypic data. Grazia Annesi, MD: Dr. Annesi contributed samples and collected phenotypic data. Soraya Bardien, PhD: Dr. Bardien contributed samples and collected phenotypic data. Maria Bozi, MD: Dr. Bozi contributed samples and collected phenotypic data. Alexis Brice, MD: Prof. Brice contributed to sample collection and collected phenotypic data. Jonathan Carr, MD: Dr. Carr contributed samples and collected phenotypic data. Sun Ju Chung, MD: Dr. Chung contributed samples and collected phenotypic data. Carl Clarke, MD: Dr. Clarke contributed samples and collected phenotypic data. David Crosiers, MD: Dr. Crosiers contributed samples and collected phenotypic data. Angela Deutschländer, MD: Dr. Deutschländer contributed samples and collected phenotypic data. Gertrud Eckstein, PhD: Dr. Eckstein contributed analysis or interpretation of data, accepts responsibility for conduct of research and will give final approval and acquisition of data. Matthew J. Farrer, PhD: Dr. Farrer contributed samples and collected phenotypic data. Stefano Goldwurm, PhD: Dr. Goldwurm contributed samples and collected phenotypic data. Gaetan Garraux, MD, PhD: Dr. Garraux contributed samples and collected phenotypic data. Georgios M. Hadjigeorgiou, MD: Dr. Hadjigeorgiou contributed samples and collected phenotypic data. Andrew A. Hicks, PhD: Dr. Hicks contributed samples and collected phenotypic data. Nobutaka Hattori, MD: Dr. Hattori contributed samples and collected phenotypic data. Christine Klein, MD: Dr. Klein contributed samples and collected phenotypic data. Beom Jeon, MD: Dr. Jeon contributed samples and collected phenotypic data. Yun Joong Kim, MD: Dr. Kim contributed samples and collected phenotypic data. Suzanne Lesage, MD: Dr. Lesage contributed samples and collected phenotypic data. Juei-Jueng Lin, MD: Dr. Lin contributed samples and collected phenotypic data. Timothy Lynch, MD: Dr. Lynch contributed samples and collected phenotypic data. Peter Lichtner, PhD: Dr. Lichtner contributed samples and collected phenotypic data. Anthony E. Lang, MD: Dr. Lang contributed samples and collected phenotypic data. Vincent Mok, MD: Dr. Mok contributed samples and collected phenotypic data. Barbara Jasinska-Myga, MD, PhD: Dr. Jasinska-Myga contributed samples and collected phenotypic data. George D. Mellick, PhD: Dr. Mellick contributed samples and collected phenotypic data and critically reviewed the manuscript. Karen E. Morrison, MD: Dr. Morrison contributed samples and collected phenotypic data. Grzegorz Opala, MD: Dr. Opala contributed samples and collected phenotypic data. Lasse Pihlstrøm, MD: Dr. Pihlstrøm contributed samples and collected phenotypic data. Peter P. Pramstaller: Dr. Pramstaller contributed samples and collected phenotypic data. Sung Sup Park, MD: Dr. Park contributed samples and collected phenotypic data. Aldo Quattrone, MD: Dr. Quattrone contributed samples and collected phenotypic data. Ekaterina Rogaeva, PhD: Dr. Rogaeva contributed samples and collected phenotypic data and participated in writing of the manuscript. Owen A. Ross, PhD: Dr. Ross contributed samples and collected phenotypic data. Leonidas Stefanis, MD: Dr. Stefanis contributed samples and collected phenotypic data. Joanne D. Stockton, PhD: Dr. Stockton contributed samples and collected phenotypic data. Peter A. Silburn, PhD: Dr. Silburn contributed samples and collected phenotypic data. Jessie Theuns, PhD: Dr. Theuns contributed samples and collected phenotypic data. Eng King Tan, MD: Dr. Tan contributed samples and collected phenotypic data. Mathias Toft, MD, PhD: Dr. Toft contributed samples and collected phenotypic data. Dr. Hiroyuki Tomiyama, MD, PhD: Dr. Tomiyama contributed samples and collected phenotypic data. Christine Van Broeckhoven, PhD: Dr. Van Broeckhoven contributed samples and collected phenotypic data. Ryan J. Uitti, MD: Dr. Uitti contributed samples and collected phenotypic data. Karin Wirdefeldt, MD: Dr. Wirdefeldt contributed samples and collected phenotypic data. Zbigniew Wszolek, MD: Dr. Wszolek contributed samples and collected phenotypic data. Georgia Xiromerisiou, MD: Dr. Xiromerisiou contributed samples and collected phenotypic data. Kuo-Chu Yueh, MD: Dr. Yueh contributed samples and collected phenotypic data. Yi Zhao, MD: Dr. Zhao contributed samples and collected phenotypic data. Thomas Gasser, MD: Dr. Gasser contributed samples and collected phenotypic data and participated in writing of the manuscript. Demetrius M. Maraganore, MD: Dr. Maraganore contributed to the administrative leadership and coordination of this study as the overall principal investigator of the Genetic Epidemiology of Parkinson's Disease Consortium and he provided critical review of the manuscript. Dr. Maraganore contributed samples and collected phenotypic data. Rejko Krüger, MD: Dr. Krüger contributed samples and collected phenotypic data and participated in writing of the manuscript. Manu Sharma, PhD: Dr. Sharma contributed to drafting and revising the manuscript for content, study concept and design, analysis and interpretation of data, acquisition of data, statistical analysis, study supervision and coordination, and obtained funding.
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