SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease
Por:
Fernández-Santiago R., Martín-Flores N., Antonelli F., Cerquera C., Moreno V., Bandres-Ciga S., Manduchi E., Tolosa E., Singleton A.B., Moore J.H., Martí M.-J., Ezquerra M., Malagelada C., Noyce A.J., Kaiyrzhanov R., Middlehurst B., Kia D.A., Tan M., Houlden H., Morris H.R., Plun-Favreau H., Holmans P., Hardy J., Trabzuni D., Bras J., Quinn J., Mok K.Y., Kinghorn K.J., Billingsley K., Wood N.W., Lewis P., Schreglmann S., Guerreiro R., Lovering R., R’Bibo L., Manzoni C., Rizig M., Ryten M., Guelfi S., Escott-Price V., Chelban V., Foltynie T., Williams N., Morrison K.E., Clarke C., Brice A., Danjou F., Lesage S., Corvol J.-C., Martinez M., Schulte C., Brockmann K., Simon-Sanchez J., Heutink P., Rizzu P., Sharma M., Gasser T., Nicolas A., Cookson M.R., Blauwendraat C., Craig D.W., Faghri F., Gibbs J.R., Hernandez D.G., Van Keuren-Jensen K., Shulman J.M., Iwaki H., Leonard H.L., Nalls M.A., Robak L., Lubbe S., Finkbeiner S., Mencacci N.E., Lungu C., Scholz S.W., Reed X., Alcalay R.N., Gan-Or Z., Rouleau G.A., Krohn L., Van Hilten J.J., Marinus J., Adarmes-Gómez A.D., Aguilar I., Alvarez I., Alvarez V., Barrero F.J., Bergareche Yarza J.A., Bernal-Bernal I., Blazquez M., Bonilla-Toribio M., Botía J.A., Boungiorno M.T., Buiza-Rueda D., Cámara A., Carrillo F., Carrión-Claro M., Cerdan D., Clarimón J., Compta Y., De La Casa B., Diez-Fairen M., Dols-Icardo O., Duarte J., Duran R., Escamilla-Sevilla F., Feliz C., Fernández M., Garcia C., García-Ruiz P., Gómez-Garre P., Gomez Heredia M.J., Gonzalez-Aramburu I., Pagola A.G., Hoenicka J., Infante J., Jesús S., Jimenez-Escrig A., Kulisevsky J., Labrador-Espinosa M.A., Lopez-Sendon J.L., De Munainarregui A.L., Macias D., Torres I.M., Marín J., Marti M.J., Mar-Tínez-castrillo J.C., Méndez-Del-barrio C., González M.M., Mata M., Mínguez A., Mir P., Rezola E.M., Muñoz E., Pagonabarraga J., Pascual-Sedano B., Pastor P., Errazquin F.P., Periñán-Tocino T., Ruiz-Martínez J., Ruz C., Rodriguez A.S., Sierra M., Suarez-Sanmartin E., Tabernero C., Tartari J.P., Tejera-Parrado C., Valldeoriola F., Vargas-González L., Vela L., Vives F., Zimprich A., Pihlstrom L., Toft M., Koks S., Taba P., Hassin-Baer S.
Publicada:
1 ene 2019
Resumen:
Background: Single nucleotide polymorphisms (SNPs) in the a-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P <.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society. © 2019 International Parkinson and Movement Disorder Society
Filiaciones:
Fernández-Santiago R.:
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, institut d’Investigacions Biomédiques August Pi i Sunyer, Catalonia, Barcelona, Spain
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain
Martín-Flores N.:
Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Catalonia, Barcelona, Spain
Institute of Neurosciences, University of Barcelona, Catalonia, Barcelona, Spain
Antonelli F.:
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Cerquera C.:
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Neurology Unit, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Medical School, Bogotá, Colombia
Moreno V.:
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Bandres-Ciga S.:
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
Instituto de investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
Manduchi E.:
The Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, United States
Tolosa E.:
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, institut d’Investigacions Biomédiques August Pi i Sunyer, Catalonia, Barcelona, Spain
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain
Singleton A.B.:
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
Moore J.H.:
The Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, United States
Martí M.-J.:
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, institut d’Investigacions Biomédiques August Pi i Sunyer, Catalonia, Barcelona, Spain
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain
Hospital Clinic Barcelona, Spain
Ezquerra M.:
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, institut d’Investigacions Biomédiques August Pi i Sunyer, Catalonia, Barcelona, Spain
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain
Hospital Clinic de Barcelona, Spain
Malagelada C.:
Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Catalonia, Barcelona, Spain
Institute of Neurosciences, University of Barcelona, Catalonia, Barcelona, Spain
Noyce A.J.:
Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, QMUL, London, United Kingdom
Department of Molecular Neuroscience, UCL, London, United Kingdom
Kaiyrzhanov R.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Middlehurst B.:
Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Kia D.A.:
UCL Genetics Institute
Tan M.:
Department of Clinical Neuroscience, University College London, London, United Kingdom
University College London, London, United Kingdom
Houlden H.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Morris H.R.:
Department of Clinical Neuroscience, University College London, London, United Kingdom
University College London, London, United Kingdom
Plun-Favreau H.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Holmans P.:
Biostatistics and Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom
Hardy J.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Trabzuni D.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
UCL Institute of Neurology, London, United Kingdom
Bras J.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
and Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Quinn J.:
Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Mok K.Y.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Kinghorn K.J.:
Institute of Healthy Ageing, University College London, London, United Kingdom
University College London, London, United Kingdom
Billingsley K.:
Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Wood N.W.:
UCL Genetics Institute
Lewis P.:
University of Reading, Reading, United Kingdom
Schreglmann S.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Guerreiro R.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
and Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Lovering R.:
University College London, London, United Kingdom
R’Bibo L.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Manzoni C.:
University of Reading, Reading, United Kingdom
Rizig M.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Ryten M.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Guelfi S.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Escott-Price V.:
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom
Chelban V.:
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
UCL Institute of Neurology, London, United Kingdom
Foltynie T.:
UCL Institute of Neurology, London, United Kingdom
Williams N.:
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom
Morrison K.E.:
Faculty of Medicine, University of Southampton, United Kingdom
Clarke C.:
University of Birmingham, Birmingham, United Kingdom
Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom
Brice A.:
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 11, 27, CNRS, UMR 72, 25, Sorbonne Universités, UPMC University Paris 06, UMR S 11, 27, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
Danjou F.:
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 11, 27, CNRS, UMR 72, 25, Sorbonne Universités, UPMC University Paris 06, UMR S 11, 27, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
Lesage S.:
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 11, 27, CNRS, UMR 72, 25, Sorbonne Universités, UPMC University Paris 06, UMR S 11, 27, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
Corvol J.-C.:
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 11, 27, CNRS, UMR 72, 25, Sorbonne Universités, UPMC University Paris 06, UMR S 11, 27, Centre d’Investigation Clinique Pitié Neurosciences CIC-14, 22, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
Martinez M.:
INSERM UMR 12, 20, Paul Sabatier University, Toulouse, France
Schulte C.:
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Tübingen, Germany
Brockmann K.:
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
Simon-Sanchez J.:
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
Heutink P.:
DZNE, German Center for Neurodegenerative Diseases and Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Rizzu P.:
DZNE, German Center for Neurodegenerative Diseases, Germany
Sharma M.:
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany
Gasser T.:
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
Nicolas A.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
Cookson M.R.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, United States
Blauwendraat C.:
National Institute on Aging and National Institute of Neurological Disorders and Stroke, United States
Craig D.W.:
Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, United States
Faghri F.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, United States
Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States
Gibbs J.R.:
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
Hernandez D.G.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
Van Keuren-Jensen K.:
Neurogenomics Division, TGen, Phoenix, AZ, United States
Shulman J.M.:
Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
Iwaki H.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
Leonard H.L.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
Nalls M.A.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, United States
CEO/Consultant Data Tecnica International, Glen Echo, MD, United States
Robak L.:
Baylor College of Medicine, Houston, Texas, United States
Lubbe S.:
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Finkbeiner S.:
Departments of Neurology and Physiology, University of California, San Francisco, CA, United States
Gladstone Institute of Neurological Disease, Taube/ Koret Center for Neurodegenerative Disease Research, San Francisco, CA, United States
Mencacci N.E.:
Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Lungu C.:
National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, United States
Scholz S.W.:
Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
Reed X.:
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
Alcalay R.N.:
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, United States
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, United States
Gan-Or Z.:
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada
Rouleau G.A.:
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada
Krohn L.:
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada
Van Hilten J.J.:
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
Marinus J.:
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
Adarmes-Gómez A.D.:
Instituto de Biome- dicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Aguilar I.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Alvarez I.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Alvarez V.:
Hospital Universitario Central de Asturias, Oviedo, Spain
Barrero F.J.:
Hospital Universitario San Cecilio de Granada, Universidad de Granada, Spain
Bergareche Yarza J.A.:
Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Bernal-Bernal I.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío, CSI SpainC, Universidad de Sevilla, Seville, Spain
Blazquez M.:
Hospital Universitario Central de Asturias, Oviedo, Spain
Bonilla-Toribio M.:
Instituto de Biome- dicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Botía J.A.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Boungiorno M.T.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Buiza-Rueda D.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Cámara A.:
Hospital Clinic de Barcelona, Spain
Carrillo F.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Carrión-Claro M.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Cerdan D.:
Hospital General de Segovia, Segovia, Spain
Clarimón J.:
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
Compta Y.:
Hospital Clinic de Barcelona, Spain
De La Casa B.:
Hospital Gregorio Marañon, Madrid, Spain
Diez-Fairen M.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Dols-Icardo O.:
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas [CIBERNED], Madrid, Spain
Duarte J.:
Hospital General de Segovia, Segovia, Spain
Duran R.:
Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain
Escamilla-Sevilla F.:
Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain
Feliz C.:
Departmento de Neurologia, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
Fernández M.:
Hospital Clinic de Barcelona, Spain
Garcia C.:
Hospital Universitario Central de Asturias, Oviedo, Spain
García-Ruiz P.:
Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
Gómez-Garre P.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Gomez Heredia M.J.:
Hospital Universitario Virgen de la Victoria, Málaga, Spain
Gonzalez-Aramburu I.:
Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain
Pagola A.G.:
Instituto de Investigación Sanitaria Bio- donostia, San Sebastián, Spain
Hoenicka J.:
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Infante J.:
Hospital Universitario Marqués de Valdecilla-IDIVAL and University of Cantabria, Santander, and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas [CIBERNED], Spain
Jesús S.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Jimenez-Escrig A.:
Hospital Universitario Ramón y Cajal, Madrid, Spain
Kulisevsky J.:
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas [CIBERNED], Spain
Labrador-Espinosa M.A.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Lopez-Sendon J.L.:
Hospital Universitario Ramón y Cajal, Madrid, Spain
De Munainarregui A.L.:
Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Macias D.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Torres I.M.:
Department of Neurology, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain
Marín J.:
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas [CIBERNED], Spain
Marti M.J.:
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, institut d’Investigacions Biomédiques August Pi i Sunyer, Catalonia, Barcelona, Spain
Neurology Service, Hospital Clinic de Barcelona, Catalonia, Barcelona, Spain
Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain
Hospital Clinic Barcelona, Spain
Mar-Tínez-castrillo J.C.:
Hospital Universitario Ramón y Cajal, Madrid, Spain
Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain
Méndez-Del-barrio C.:
Instituto de Biome- dicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
González M.M.:
Hospital Universitario Central de Asturias, Oviedo, Spain
Mata M.:
Department of Neurology, Hospital Universitario Infanta Sofía, Madrid, Spain
Mínguez A.:
Hospital Universitario Virgen de las Nieves, Granada, Instituto de Investigación Biosanitaria de Granada, Spain
Mir P.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain
Rezola E.M.:
Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Muñoz E.:
Hospital Clinic Barcelona, Spain
Pagonabarraga J.:
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas [CIBERNED], Spain
Pascual-Sedano B.:
Unidad de Trastornos del Movimiento, Hospital Sant Pau, Barcelona, Spain
Pastor P.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Errazquin F.P.:
Hospital Universitario Virgen de la Victoria, Málaga, Spain
Periñán-Tocino T.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Ruiz-Martínez J.:
Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Hospital Universitario Donostia, Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Ruz C.:
Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain
Rodriguez A.S.:
Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain
Sierra M.:
Hospital Universitario Marqués de Valdecilla-Instituto de Investigacion Valdecilla (IDIVAL), Santander, Spain
Suarez-Sanmartin E.:
Hospital Universitario Central de Asturias, Oviedo, Spain
Tabernero C.:
Hospital General de Segovia, Segovia, Spain
Tartari J.P.:
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Tejera-Parrado C.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Valldeoriola F.:
Hospital Clinic Barcelona, Spain
Vargas-González L.:
Instituto de Biomedicina de Sevilla [IBiS], Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Vela L.:
Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain
Vives F.:
Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain
Zimprich A.:
Department of Neurology, Medical University of Vienna, Austria
Pihlstrom L.:
Department of Neurology, Oslo University Hospital, Oslo, Norway
Toft M.:
Department of Neurology and Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway
Koks S.:
Department of Pathophysiology, University of Tartu, Tartu, Estonia
Department of Reproductive Biology, Estonian University of Life Sciences, Tartu, Estonia
Taba P.:
Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
Hassin-Baer S.:
The Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel- Hashomer, 52, 62, 10, 1, Ramat Gan, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Green Accepted, All Open Access; Green
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