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Parkinson Disease: HELP
Articles by Javier Simon-Sanchez
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, J. Simón-Sánchez wrote the following 21 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Editorial Parkinson disease GWAS: the question of lumping or splitting is back again. 2015

Simón-Sánchez, Javier / Gasser, Thomas. ·From Genetics and Epigenetics of Neurodegeneration (J.S.-S.) and Department of Neurodegenerative Diseases (T.G.), Hertie Institute for Clinical Brain Research, University of Tübingen · and German Center for Neurodegenerative Diseases (J.S.-S., T.G.), Tübingen, Germany. ·Neurology · Pubmed #25663226.

ABSTRACT: -- No abstract --

2 Article The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. 2019

Bandres-Ciga, Sara / Ahmed, Sarah / Sabir, Marya S / Blauwendraat, Cornelis / Adarmes-Gómez, Astrid D / Bernal-Bernal, Inmaculada / Bonilla-Toribio, Marta / Buiza-Rueda, Dolores / Carrillo, Fátima / Carrión-Claro, Mario / Gómez-Garre, Pilar / Jesús, Silvia / Labrador-Espinosa, Miguel A / Macias, Daniel / Méndez-Del-Barrio, Carlota / Periñán-Tocino, Teresa / Tejera-Parrado, Cristina / Vargas-González, Laura / Diez-Fairen, Monica / Alvarez, Ignacio / Tartari, Juan Pablo / Buongiorno, Mariateresa / Aguilar, Miquel / Gorostidi, Ana / Bergareche, Jesús Alberto / Mondragon, Elisabet / Vinagre-Aragon, Ana / Croitoru, Ioana / Ruiz-Martínez, Javier / Dols-Icardo, Oriol / Kulisevsky, Jaime / Marín-Lahoz, Juan / Pagonabarraga, Javier / Pascual-Sedano, Berta / Ezquerra, Mario / Cámara, Ana / Compta, Yaroslau / Fernández, Manel / Fernández-Santiago, Rubén / Muñoz, Esteban / Tolosa, Eduard / Valldeoriola, Francesc / Gonzalez-Aramburu, Isabel / Sanchez Rodriguez, Antonio / Sierra, María / Menéndez-González, Manuel / Blazquez, Marta / Garcia, Ciara / Suarez-San Martin, Esther / García-Ruiz, Pedro / Martínez-Castrillo, Juan Carlos / Vela-Desojo, Lydia / Ruz, Clara / Barrero, Francisco Javier / Escamilla-Sevilla, Francisco / Mínguez-Castellanos, Adolfo / Cerdan, Debora / Tabernero, Cesar / Gomez Heredia, Maria Jose / Perez Errazquin, Francisco / Romero-Acebal, Manolo / Feliz, Cici / Lopez-Sendon, Jose Luis / Mata, Marina / Martínez Torres, Irene / Kim, Jonggeol Jeffrey / Dalgard, Clifton L / Anonymous1451065 / Brooks, Janet / Saez-Atienzar, Sara / Gibbs, J Raphael / Jorda, Rafael / Botia, Juan A / Bonet-Ponce, Luis / Morrison, Karen E / Clarke, Carl / Tan, Manuela / Morris, Huw / Edsall, Connor / Hernandez, Dena / Simon-Sanchez, Javier / Nalls, Mike A / Scholz, Sonja W / Jimenez-Escrig, Adriano / Duarte, Jacinto / Vives, Francisco / Duran, Raquel / Hoenicka, Janet / Alvarez, Victoria / Infante, Jon / Marti, Maria José / Clarimón, Jordi / López de Munain, Adolfo / Pastor, Pau / Mir, Pablo / Singleton, Andrew / Anonymous1461065. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Seville, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. · Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, Barcelona, Spain. · Neurodegenerative Disorders Area, Biodonostia Health Research Institute, San Sebastián, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Plataforma de Genomica, Instituto de Investigacion Biodonostia, San Sebastián, Spain. · Unidad de Trastornos de Movimiento, Departamento de Neurologia, Hospital Universitario de Donostia, San Sebastián, Spain. · Genetics of Neurodegenerative Disorders Unit, IIB Sant Pau, and Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Lab. of Parkinson disease and Other Neurodegenerative Movement Disorders, IDIBAPS-Institut d'Investigacions Biomèdiques, Barcelona, Catalonia, Spain. · Unitat de Parkinson i Trastorns del Moviment. Servicio de Neurologia, Hospital Clínic de Barcelona and Institut de Neurociencies de la Universitat de Barcelona (Maria de Maetzu Center), Catalonia, Spain. · Servicio de Neurología, Hospital Universitario Marqués de Valdecilla (IDIVAL) and Universidad de Cantabria, Santander, Spain. · Servicio de Neurología, Hospital Universitario Central de Asturias, Asturias, Spain. · Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain. · Departamento de Neurologia, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Servicio de Neurologia, Hospital Universitario Fundación Alcorcón, Madrid, Spain. · Centro de Investigacion Biomedica and Departamento de Fisiologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. · Servicio de Neurología, Hospital Universitario San Cecilio, Granada, Universidad de Granada, Spain. · Servicio de Neurología, Hospital Universitario Virgen de las Nieves, Granada, Spain. · Servicio de Neurología, Hospital General de Segovia, Segovia, Spain. · Servicio de Neurología, Hospital Universitario Virgen de la Victoria, Malaga, Spain. · Departamento de Neurologia, Hospital Universitario Infanta Sofía, Madrid, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain. · Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain. · Department of Molecular Neuroscience, UCL, Institute of Neurology, London, United Kingdom. · Department of Neurology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. · University of Birmingham, Birmingham, United Kingdom. · Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. · Department of Clinical Neuroscience, University College London, London, United Kingdom. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. · Data Tecnica International, Glen Echo, Maryland, USA. · Department of Neurology, Johns Hopkins Medical Center, Baltimore, Maryland, USA. · Laboratorio de Neurogenética y Medicina Molecular, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain. · Laboratorio de Genética, Hospital Universitario Central de Asturias, Asturias, Spain. · Departamento de Neurociencias. UPV-EHU, Servicio de Neurología, Hospital Universitario Donostia, San Sebastián, Spain. ·Mov Disord · Pubmed #31660654.

ABSTRACT: BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

3 Article A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. 2019

van der Lee, Sven J / Conway, Olivia J / Jansen, Iris / Carrasquillo, Minerva M / Kleineidam, Luca / van den Akker, Erik / Hernández, Isabel / van Eijk, Kristel R / Stringa, Najada / Chen, Jason A / Zettergren, Anna / Andlauer, Till F M / Diez-Fairen, Monica / Simon-Sanchez, Javier / Lleó, Alberto / Zetterberg, Henrik / Nygaard, Marianne / Blauwendraat, Cornelis / Savage, Jeanne E / Mengel-From, Jonas / Moreno-Grau, Sonia / Wagner, Michael / Fortea, Juan / Keogh, Michael J / Blennow, Kaj / Skoog, Ingmar / Friese, Manuel A / Pletnikova, Olga / Zulaica, Miren / Lage, Carmen / de Rojas, Itziar / Riedel-Heller, Steffi / Illán-Gala, Ignacio / Wei, Wei / Jeune, Bernard / Orellana, Adelina / Then Bergh, Florian / Wang, Xue / Hulsman, Marc / Beker, Nina / Tesi, Niccolo / Morris, Christopher M / Indakoetxea, Begoña / Collij, Lyduine E / Scherer, Martin / Morenas-Rodríguez, Estrella / Ironside, James W / van Berckel, Bart N M / Alcolea, Daniel / Wiendl, Heinz / Strickland, Samantha L / Pastor, Pau / Rodríguez Rodríguez, Eloy / Anonymous1381184 / Anonymous1391184 / Anonymous1401184 / Anonymous1411184 / Anonymous1421184 / Anonymous1431184 / Boeve, Bradley F / Petersen, Ronald C / Ferman, Tanis J / van Gerpen, Jay A / Reinders, Marcel J T / Uitti, Ryan J / Tárraga, Lluís / Maier, Wolfgang / Dols-Icardo, Oriol / Kawalia, Amit / Dalmasso, Maria Carolina / Boada, Mercè / Zettl, Uwe K / van Schoor, Natasja M / Beekman, Marian / Allen, Mariet / Masliah, Eliezer / de Munain, Adolfo López / Pantelyat, Alexander / Wszolek, Zbigniew K / Ross, Owen A / Dickson, Dennis W / Graff-Radford, Neill R / Knopman, David / Rademakers, Rosa / Lemstra, Afina W / Pijnenburg, Yolande A L / Scheltens, Philip / Gasser, Thomas / Chinnery, Patrick F / Hemmer, Bernhard / Huisman, Martijn A / Troncoso, Juan / Moreno, Fermin / Nohr, Ellen A / Sørensen, Thorkild I A / Heutink, Peter / Sánchez-Juan, Pascual / Posthuma, Danielle / Anonymous1441184 / Clarimón, Jordi / Christensen, Kaare / Ertekin-Taner, Nilüfer / Scholz, Sonja W / Ramirez, Alfredo / Ruiz, Agustín / Slagboom, Eline / van der Flier, Wiesje M / Holstege, Henne. ·Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl. · Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany. · DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany. · Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. · Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. · Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. · Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. · Interdepartmental Program in Bioinformatics, University of California, Los Angeles, USA. · Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AgeCap) at the University of Gothenburg, Gothenburg, Sweden. · Max Planck Institute of Psychiatry, Munich, Germany. · Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany. · Movement Disorders and Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain. · Fundacio per la Recerca Biomedica I Social Mutua Terrassa, Terrassa, Barcelona, Spain. · German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. · The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, 20892-3707, USA. · Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. · Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK. · Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA. · Instituto Biodonostia, San Sebastian, Spain. · University Hospital "Marques de Valdecilla", Santander, Spain. · IDIVAL, Santander, Spain. · Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany. · Department of Neurology, University of Leipzig, Leipzig, Germany. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Newcastle Brain Tissue Resource, Edwardson Building, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK. · Cognitive Disorders Unit, Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain. · Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department of Primary Medical Care, Center for Psychosocial Medicine, University Medical Center, Hamburg-Eppendorf, Germany. · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH4 2XU, UK. · Department of Neurology, Klinik für Neurologie mit Institut für Translationale Neurologie, University of Münster, Münster, Germany. · Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, 55905, USA. · Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. · Fundación Instituto Leloir-IIBBA-CONICET, Buenos Aires, Argentina. · Department of Neurology, University of Rostock, Rostock, Germany. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, 21287, USA. · Center of Neurology, Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK. · Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. · Department of Sociology, VU University, Amsterdam, The Netherlands. · Research Unit of Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. · Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Copenhagen, Denmark. · Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · MRC Integrative Epidemiology Unit, Bristol University, Bristol, UK. · Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. · Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. · Dutch Society for Research on Ageing, Leiden, The Netherlands. · Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl. ·Acta Neuropathol · Pubmed #31131421.

ABSTRACT: The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

4 Article Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. 2019

Blauwendraat, Cornelis / Heilbron, Karl / Vallerga, Costanza L / Bandres-Ciga, Sara / von Coelln, Rainer / Pihlstrøm, Lasse / Simón-Sánchez, Javier / Schulte, Claudia / Sharma, Manu / Krohn, Lynne / Siitonen, Ari / Iwaki, Hirotaka / Leonard, Hampton / Noyce, Alastair J / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Scholz, Sonja W / Jankovic, Joseph / Shulman, Lisa M / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / van Hilten, Jacobus J / Marinus, Johan / Anonymous861129 / Eerola-Rautio, Johanna / Tienari, Pentti / Majamaa, Kari / Toft, Mathias / Grosset, Donald G / Gasser, Thomas / Heutink, Peter / Shulman, Joshua M / Wood, Nicolas / Hardy, John / Morris, Huw R / Hinds, David A / Gratten, Jacob / Visscher, Peter M / Gan-Or, Ziv / Nalls, Mike A / Singleton, Andrew B / Anonymous871129. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · 23andMe, Inc., Mountain View, California, USA. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · The Michael J Fox Foundation for Parkinson's Research, New York, New York, USA. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom. · Departments of Molecular & Human Genetics and Neuroscience, Baylor College of Medicine, Houston, Texas, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. · Mater Research, Translational Research Institute, Brisbane, Queensland, Australia. · Queensland Brain Institute, The University of Queensland, Brisbane, Australia. · Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #30957308.

ABSTRACT: BACKGROUND: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. OBJECTIVES: To identify the genetic determinants of PD age at onset. METHODS: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. RESULTS: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. CONCLUSIONS: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

5 Article Role of LRRK2 and SNCA in autosomal dominant Parkinson's disease in Turkey. 2018

Kessler, Christoph / Atasu, Burcu / Hanagasi, Hasmet / Simón-Sánchez, Javier / Hauser, Ann-Kathrin / Pak, Meltem / Bilgic, Basar / Erginel-Unaltuna, Nihan / Gurvit, Hakan / Gasser, Thomas / Lohmann, Ebba. ·Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Institute for Experimental Medical Research, Istanbul University, Turkey. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address: ebbalohmann@gmx.net. ·Parkinsonism Relat Disord · Pubmed #29248340.

ABSTRACT: INTRODUCTION: Mutations in the LRRK2 and alpha-synuclein (SNCA) genes are well-established causes of autosomal dominant Parkinson's disease (PD). However, their frequency differs widely between ethnic groups. Only three studies have screened all coding regions of LRRK2 and SNCA in European samples so far. In Turkey, the role of LRRK2 in Parkinson's disease has been studied fragmentarily, and the incidence of SNCA copy number variations is unknown. The purpose of this study is to determine the frequency of LRRK2 and SNCA mutations in autosomal dominant PD in Turkey. METHODS: We performed Sanger sequencing of all coding LRRK2 and SNCA exons in a sample of 91 patients with Parkinsonism. Copy number variations in SNCA, PRKN, PINK1, DJ1 and ATP13A2 were assessed using the MLPA method. All patients had a positive family history compatible with autosomal dominant inheritance. RESULTS: Known mutations in LRRK2 and SNCA were found in 3.3% of cases: one patient harbored the LRRK2 G2019S mutation, and two patients carried a SNCA gene duplication. Furthermore, we found a heterozygous deletion of PRKN exon 2 in one patient, and four rare coding variants of unknown significance (LRRK2: A211V, R1067Q, T2494I; SNCA: T72T). Genetic testing in one affected family identified the LRRK2 R1067Q variant as a possibly pathogenic substitution. CONCLUSION: Point mutations in LRRK2 and SNCA are a rare cause of autosomal dominant PD in Turkey. However, copy number variations should be considered. The unclassified variants, especially LRRK2 R1067Q, demand further investigation.

6 Article Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. 2017

Jansen, Iris E / Ye, Hui / Heetveld, Sasja / Lechler, Marie C / Michels, Helen / Seinstra, Renée I / Lubbe, Steven J / Drouet, Valérie / Lesage, Suzanne / Majounie, Elisa / Gibbs, J Raphael / Nalls, Mike A / Ryten, Mina / Botia, Juan A / Vandrovcova, Jana / Simon-Sanchez, Javier / Castillo-Lizardo, Melissa / Rizzu, Patrizia / Blauwendraat, Cornelis / Chouhan, Amit K / Li, Yarong / Yogi, Puja / Amin, Najaf / van Duijn, Cornelia M / Anonymous931133 / Morris, Huw R / Brice, Alexis / Singleton, Andrew B / David, Della C / Nollen, Ellen A / Jain, Shushant / Shulman, Joshua M / Heutink, Peter. ·German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. · Graduate School of Cellular & Molecular Neuroscience, Tübingen, 72074, Germany. · European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Northwestern University Feinberg School of Medicine, Ken and Ruth Davee Department of Neurology, Chicago, IL, USA. · Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Medical & Molecular Genetics, King's College London, London, UK. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund St., N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. Peter.Heutink@dzne.de. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. Peter.Heutink@dzne.de. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Peter.Heutink@dzne.de. ·Genome Biol · Pubmed #28137300.

ABSTRACT: BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.

7 Article Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. 2017

Giri, Anamika / Mok, Kin Y / Jansen, Iris / Sharma, Manu / Tesson, Christelle / Mangone, Graziella / Lesage, Suzanne / Bras, José M / Shulman, Joshua M / Sheerin, Una-Marie / Anonymous5870886 / Díez-Fairen, Mónica / Pastor, Pau / Martí, María José / Ezquerra, Mario / Tolosa, Eduardo / Correia-Guedes, Leonor / Ferreira, Joaquim / Amin, Najaf / van Duijn, Cornelia M / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Nalls, Michael / Simón-Sánchez, Javier. ·Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France. · Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. · Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain. · Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Department of Neurosciences, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal. · Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. · Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Department of Neurosciences, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Electronic address: javier.simon-sanchez@dzne.de. ·Neurobiol Aging · Pubmed #27818000.

ABSTRACT: Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.

8 Article Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data. 2016

Mok, Kin Y / Sheerin, Una / Simón-Sánchez, Javier / Salaka, Afnan / Chester, Lucy / Escott-Price, Valentina / Mantripragada, Kiran / Doherty, Karen M / Noyce, Alastair J / Mencacci, Niccolo E / Lubbe, Steven J / Anonymous8211124 / Williams-Gray, Caroline H / Barker, Roger A / van Dijk, Karin D / Berendse, Henk W / Heutink, Peter / Corvol, Jean-Christophe / Cormier, Florence / Lesage, Suzanne / Brice, Alexis / Brockmann, Kathrin / Schulte, Claudia / Gasser, Thomas / Foltynie, Thomas / Limousin, Patricia / Morrison, Karen E / Clarke, Carl E / Sawcer, Stephen / Warner, Tom T / Lees, Andrew J / Morris, Huw R / Nalls, Mike A / Singleton, Andrew B / Hardy, John / Abramov, Andrey Y / Plagnol, Vincent / Williams, Nigel M / Wood, Nicholas W. ·Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, China. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; Genetics and Epigenetics of Neurodegeneration, Tübingen, Germany. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK; Medical Genetics and Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. · Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK; Department of Regional Neurosciences, Royal Victoria Hospital, Belfast, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK. · Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands. · Genome Biology of Neurodegenerative Diseases, Tübingen, Germany. · Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Center for Scientific Research (CNRS), and Research Unit UMR_S 1127 at Pierre and Marie Curie University University of Paris VI at Sorbonne Universités, Institut du Cerveau et de la Moelle épinière Brain and Spine Institute (ICM), Paris, France; Clinical Investigation Center Unit 1422 at INSERM and AP-HP Hôpital de la Pitié Salpêtrière, Centre d'Investigation Clinique Pitié Neurosciences, Paris, France. · Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. · Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK. · Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. · School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. · Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK. · Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · UCL Genetics Institute, London, UK. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. Electronic address: williamsnm@cf.ac.uk. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: n.wood@ucl.ac.uk. ·Lancet Neurol · Pubmed #27017469.

ABSTRACT: BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. FUNDING: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

9 Article A novel homozygous DJ1 mutation causes parkinsonism and ALS in a Turkish family. 2016

Hanagasi, Hasmet A / Giri, Anamika / Kartal, Ece / Guven, Gamze / Bilgiç, Başar / Hauser, Ann-Kathrin / Emre, Murat / Heutink, Peter / Basak, Nazlı / Gasser, Thomas / Simón-Sánchez, Javier / Lohmann, Ebba. ·Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Capa, 34390 Istanbul, Turkey. Electronic address: hasmet@yahoo.com. · Dept. of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. · Department Molecular Biology and Genetics, Neurodegeneration Research Laboratory, Bogazici University, 34342, Istanbul, Turkey. · Institute for Experimental Medicine, Genetics Department, Istanbul University, Istanbul, Turkey. · Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Capa, 34390 Istanbul, Turkey. · Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Capa, 34390 Istanbul, Turkey; Dept. of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. ·Parkinsonism Relat Disord · Pubmed #26972524.

ABSTRACT: OBJECTIVE: DJ1 mutations (PARK7) are among the monogenic causes of early-onset autosomal recessive parkinsonism. Here, we report clinical and genetic findings in a family with Turkish origin carrying a new DJ1 mutation and presenting with early-onset levodopa responsive parkinsonism and signs of amyotrophic lateral sclerosis (ALS). METHODS: The family consisted of 12 members including 10 offsprings of whom three were affected. All family members underwent detailed clinical examination. DNA samples from the index case, his unaffected sister, and his parents were subjected to whole genome sequencing analysis. RESULTS: The index case 38-year-old man developed left hand tremor at the age of 24 years. He had progressive asymmetrical parkinsonism, depression and developed signs of ALS within 4 years. His two affected sisters had young-onset asymmetrical tremor-dominant parkinsonism with signs of ALS. A new homozygous p.Q45X mutation in exon 3 in DJ1 was found in all three patients. Their unaffected parents and one clinically healthy sibling were found to be heterozygous for this mutation. CONCLUSIONS: This is the second report of DJ1 mutations associated with parkinsonism and ALS. This is relevant for genetic counseling as well as for understanding the pathogenesis of the broad spectrum of parkinsonism-ALS disease complex.

10 Article Variation in PARK10 is not associated with risk and age at onset of Parkinson's disease in large clinical cohorts. 2015

Simón-Sánchez, Javier / Heutink, Peter / Gasser, Thomas / Anonymous630839. ·Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Genetics and Epigenetics of Neurodegeneration, German Center for Neurodegenerative diseases (DZNE)-Tübingen, Tübingen, Germany. Electronic address: javier.simon-sanchez@dzne.de. · Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative diseases (DZNE)-Tübingen, Tübingen, Germany. ·Neurobiol Aging · Pubmed #26260214.

ABSTRACT: A recent study in autopsy-confirmed Parkinson's disease (PD) patients and controls revived the debate about the role of PARK10 in this disorder. In an attempt to replicate these results and further understand the role of this locus in the risk and age at onset of PD, we decided to explore NeuroX genotyping and whole exome sequencing data from 2 large independent cohorts of clinical patients and controls from the International Parkinson's Disease Genomic Consortium. A series of single-variant and gene-based aggregation (sequence kernel association test and combined multivariate and collapsing test) statistical tests suggested that common and rare genetic variation in this locus do not influence the risk or age at onset of clinical PD.

11 Article Accurate prediction of a minimal region around a genetic association signal that contains the causal variant. 2014

Bochdanovits, Zoltán / Simón-Sánchez, Javier / Jonker, Marianne / Hoogendijk, Witte J / van der Vaart, Aad / Heutink, Peter. ·Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. · Section Stochastics, Department of Mathematics, Faculty of Sciences, Vrije Universiteit, Amsterdam, The Netherlands. · 1] Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands. ·Eur J Hum Genet · Pubmed #23736218.

ABSTRACT: In recent years, genome-wide association studies have been very successful in identifying loci for complex traits. However, typically these findings involve noncoding and/or intergenic SNPs without a clear functional effect that do not directly point to a gene. Hence, the challenge is to identify the causal variant responsible for the association signal. Typically, the first step is to identify all genetic variation in the locus region, usually by resequencing a large number of case chromosomes. Among all variants, the causal one needs to be identified in further functional studies. Because the experimental follow up can be very laborious, restricting the number of variants to be scrutinized can yield a great advantage. An objective method for choosing the size of the region to be followed up would be highly valuable. Here, we propose a simple method to call the minimal region around a significant association peak that is very likely to contain the causal variant. We model linkage disequilibrium (LD) in cases from the observed single SNP association signals, and predict the location of the causal variant by quantifying how well this relationship fits the data. Simulations showed that our approach identifies genomic regions of on average ∼50 kb with up to 90% probability to contain the causal variant. We apply our method to two genome-wide association data sets and localize both the functional variant REP1 in the α-synuclein gene that conveys susceptibility to Parkinson's disease and the APOE gene responsible for the association signal in the Alzheimer's disease data set.

12 Article Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. 2013

Trabzuni, Daniah / Ryten, Mina / Emmett, Warren / Ramasamy, Adaikalavan / Lackner, Karl J / Zeller, Tanja / Walker, Robert / Smith, Colin / Lewis, Patrick A / Mamais, Adamantios / de Silva, Rohan / Vandrovcova, Jana / Anonymous7151107 / Hernandez, Dena / Nalls, Michael A / Sharma, Manu / Garnier, Sophie / Lesage, Suzanne / Simon-Sanchez, Javier / Gasser, Thomas / Heutink, Peter / Brice, Alexis / Singleton, Andrew / Cai, Huaibin / Schadt, Eric / Wood, Nicholas W / Bandopadhyay, Rina / Weale, Michael E / Hardy, John / Plagnol, Vincent. ·Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom. ·PLoS One · Pubmed #23967090.

ABSTRACT: Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms.

13 Article Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk. 2013

Moskvina, Valentina / Harold, Denise / Russo, GianCarlo / Vedernikov, Alexey / Sharma, Manu / Saad, Mohamed / Holmans, Peter / Bras, Jose M / Bettella, Francesco / Keller, Margaux F / Nicolaou, Nayia / Simón-Sánchez, Javier / Gibbs, J Raphael / Schulte, Claudia / Durr, Alexandra / Guerreiro, Rita / Hernandez, Dena / Brice, Alexis / Stefánsson, Hreinn / Majamaa, Kari / Gasser, Thomas / Heutink, Peter / Wood, Nick / Martinez, Maria / Singleton, Andrew B / Nalls, Michael A / Hardy, John / Owen, Michael J / O'Donovan, Michael C / Williams, Julie / Morris, Huw R / Williams, Nigel M / Anonymous4501124. · ·JAMA Neurol · Pubmed #23921447.

ABSTRACT: IMPORTANCE: Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. OBJECTIVE: To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. DESIGN: Combined GWA analysis. SETTING: Data sets from the United Kingdom, Germany, France, and the United States. PARTICIPANTS: Thousands of patients with AD or PD and their controls. MAIN OUTCOMES AND MEASURES: Meta-analysis of GWA studies of AD and PD. METHODS: To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. RESULTS: Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. CONCLUSIONS AND RELEVANCE: Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.

14 Article The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism. 2013

Klebe, Stephan / Golmard, Jean-Louis / Nalls, Michael A / Saad, Mohamad / Singleton, Andrew B / Bras, Jose M / Hardy, John / Simon-Sanchez, Javier / Heutink, Peter / Kuhlenbäumer, Gregor / Charfi, Rim / Klein, Christine / Hagenah, Johann / Gasser, Thomas / Wurster, Isabel / Lesage, Suzanne / Lorenz, Delia / Deuschl, Günther / Durif, Franck / Pollak, Pierre / Damier, Philippe / Tison, François / Durr, Alexandra / Amouyel, Philippe / Lambert, Jean-Charles / Tzourio, Christophe / Maubaret, Cécilia / Charbonnier-Beaupel, Fanny / Tahiri, Khadija / Vidailhet, Marie / Martinez, Maria / Brice, Alexis / Corvol, Jean-Christophe / Anonymous2881022 / Anonymous2891022. ·Centre d'Investigation Clinique, Institut du Cerveau et de la Moelle épinière, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris 75651 Cedex 13, France. ·J Neurol Neurosurg Psychiatry · Pubmed #23408064.

ABSTRACT: The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.

15 Article A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. 2013

Holmans, Peter / Moskvina, Valentina / Jones, Lesley / Sharma, Manu / Anonymous2830744 / Vedernikov, Alexey / Buchel, Finja / Saad, Mohamad / Bras, Jose M / Bettella, Francesco / Nicolaou, Nayia / Simón-Sánchez, Javier / Mittag, Florian / Gibbs, J Raphael / Schulte, Claudia / Durr, Alexandra / Guerreiro, Rita / Hernandez, Dena / Brice, Alexis / Stefánsson, Hreinn / Majamaa, Kari / Gasser, Thomas / Heutink, Peter / Wood, Nicholas W / Martinez, Maria / Singleton, Andrew B / Nalls, Michael A / Hardy, John / Morris, Huw R / Williams, Nigel M. ·Department of Psychological Medicine and Neurology, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK. ·Hum Mol Genet · Pubmed #23223016.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.

16 Article Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. 2012

Keller, Margaux F / Saad, Mohamad / Bras, Jose / Bettella, Francesco / Nicolaou, Nayia / Simón-Sánchez, Javier / Mittag, Florian / Büchel, Finja / Sharma, Manu / Gibbs, J Raphael / Schulte, Claudia / Moskvina, Valentina / Durr, Alexandra / Holmans, Peter / Kilarski, Laura L / Guerreiro, Rita / Hernandez, Dena G / Brice, Alexis / Ylikotila, Pauli / Stefánsson, Hreinn / Majamaa, Kari / Morris, Huw R / Williams, Nigel / Gasser, Thomas / Heutink, Peter / Wood, Nicholas W / Hardy, John / Martinez, Maria / Singleton, Andrew B / Nalls, Michael A / Anonymous1690734 / Anonymous1700734. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. ·Hum Mol Genet · Pubmed #22892372.

ABSTRACT: Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

17 Article Use of support vector machines for disease risk prediction in genome-wide association studies: concerns and opportunities. 2012

Mittag, Florian / Büchel, Finja / Saad, Mohamad / Jahn, Andreas / Schulte, Claudia / Bochdanovits, Zoltan / Simón-Sánchez, Javier / Nalls, Mike A / Keller, Margaux / Hernandez, Dena G / Gibbs, J Raphael / Lesage, Suzanne / Brice, Alexis / Heutink, Peter / Martinez, Maria / Wood, Nicholas W / Hardy, John / Singleton, Andrew B / Zell, Andreas / Gasser, Thomas / Sharma, Manu / Anonymous3331107. ·Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tübingen, Germany. ·Hum Mutat · Pubmed #22777693.

ABSTRACT: The success of genome-wide association studies (GWAS) in deciphering the genetic architecture of complex diseases has fueled the expectations whether the individual risk can also be quantified based on the genetic architecture. So far, disease risk prediction based on top-validated single-nucleotide polymorphisms (SNPs) showed little predictive value. Here, we applied a support vector machine (SVM) to Parkinson disease (PD) and type 1 diabetes (T1D), to show that apart from magnitude of effect size of risk variants, heritability of the disease also plays an important role in disease risk prediction. Furthermore, we performed a simulation study to show the role of uncommon (frequency 1-5%) as well as rare variants (frequency <1%) in disease etiology of complex diseases. Using a cross-validation model, we were able to achieve predictions with an area under the receiver operating characteristic curve (AUC) of ~0.88 for T1D, highlighting the strong heritable component (∼90%). This is in contrast to PD, where we were unable to achieve a satisfactory prediction (AUC ~0.56; heritability ~38%). Our simulations showed that simultaneous inclusion of uncommon and rare variants in GWAS would eventually lead to feasible disease risk prediction for complex diseases such as PD. The used software is available at http://www.ra.cs.uni-tuebingen.de/software/MACLEAPS/.

18 Article Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease. 2012

Simón-Sánchez, Javier / Kilarski, Laura L / Nalls, Michael A / Martinez, Maria / Schulte, Claudia / Holmans, Peter / Anonymous2841124 / Anonymous2851124 / Gasser, Thomas / Hardy, John / Singleton, Andrew B / Wood, Nicholas W / Brice, Alexis / Heutink, Peter / Williams, Nigel / Morris, Huw R. ·Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. ·PLoS One · Pubmed #22427796.

ABSTRACT: Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity.We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort.There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis.

19 Article Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. 2011

Anonymous1361022 / Nalls, Michael A / Plagnol, Vincent / Hernandez, Dena G / Sharma, Manu / Sheerin, Una-Marie / Saad, Mohamad / Simón-Sánchez, J / Schulte, Claudia / Lesage, Suzanne / Sveinbjörnsdóttir, Sigurlaug / Stefánsson, Kári / Martinez, Maria / Hardy, John / Heutink, Peter / Brice, Alexis / Gasser, Thomas / Singleton, Andrew B / Wood, Nicholas W. · ·Lancet · Pubmed #21292315.

ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. FINDINGS: The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7-69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23-2·83) compared with 1·00 in the lowest quintile of disease risk. INTERPRETATION: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. FUNDING: Wellcome Trust, National Institute on Aging, and US Department of Defense.

20 Article Genome-wide association study confirms extant PD risk loci among the Dutch. 2011

Simón-Sánchez, Javier / van Hilten, Jacobus J / van de Warrenburg, Bart / Post, Bart / Berendse, Henk W / Arepalli, Sampath / Hernandez, Dena G / de Bie, Rob M A / Velseboer, Daan / Scheffer, Hans / Bloem, Bas / van Dijk, Karin D / Rivadeneira, Fernando / Hofman, Albert / Uitterlinden, André G / Rizzu, Patrizia / Bochdanovits, Zoltan / Singleton, Andrew B / Heutink, Peter. ·Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, The Netherlands. j.simonsanchez@vumc.nl ·Eur J Hum Genet · Pubmed #21248740.

ABSTRACT: In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514,799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P = 1.63 × 10(-5), OR = 1.325 and BST1, rs12502586: P = 1.63 × 10(-3), OR = 1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P = 1.22 × 10(-4), OR = 1.51; HLA, rs4248166: P = 4.39 × 10(-5), OR = 1.36; and MAPT, rs3785880: P = 1.9 × 10(-3), OR = 1.19).

21 Minor ADORA1 mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies. 2017

Blauwendraat, Cornelis / Nalls, Mike A / Federoff, Monica / Pletnikova, Olga / Ding, Jinhui / Letson, Christopher / Geiger, Joshua T / Gibbs, J Raphael / Hernandez, Dena G / Troncoso, Juan C / Simón-Sánchez, Javier / Scholz, Sonja W / Anonymous6391022. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Contractor/consultant with Kelly Services, Rockville, Maryland, USA. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA. ·Mov Disord · Pubmed #27987235.

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