Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
Storm C.S. Kia D.A. Almramhi M.M. Bandres-Ciga S. Finan C. Noyce A.J. Kaiyrzhanov R. Middlehurst B. Tan M. Houlden H. Morris H.R. Plun-Favreau H. Holmans P. Hardy J. Trabzuni D. Quinn J. Bubb V. Mok K.Y. Kinghorn K.J. Lewis P. Schreglmann S.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. Harvey K. Jacobs B.M. Brice A. Danjou F. Lesage S. Corvol J.-C. Martinez M. Schulte C. Brockmann K. Simón-Sánchez J. Heutink P. Rizzu P. Sharma M. Gasser T. Schneider S.A. Cookson M.R. Blauwendraat C. Craig D.W. Billingsley K. Makarious M.B. Narendra D.P. 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. Bras J. Guerreiro R. Lubbe S. Troycoco T. Finkbeiner S. Mencacci N.E. Lungu C. Singleton A.B. Scholz S.W. Reed X. Uitti R.J. Ross O.A. Grenn F.P. Moore A. Alcalay R.N. Wszolek Z.K. Gan-Or Z. Rouleau G.A. Krohn L. Mufti K. van Hilten J.J. Marinus J. Adarmes-Gómez A.D. Aguilar M. Alvarez I. Alvarez V. Barrero F.J. Yarza J.A.B. 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. Diez-Fairen M. Dols-Icardo O. Duarte J. Duran R. Escamilla-Sevilla F. Ezquerra M. Feliz C. Fernández M. Fernández-Santiago R. Garcia C. García-Ruiz P. Gómez-Garre P. Heredia M.J.G. 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 Munain Arregui A.L. Macias D. Torres I.M. Marín J. Marti M.J. Martínez-Castrillo J.C. Méndez-del-Barrio C. González M.M. Mata M. Mínguez A. Mir P. Rezola E.M. Muñoz E. Pagonabarraga J. 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. Tolosa E. Valldeoriola F. Vargas-González L. Vela L. Vives F. Zimprich A. Pihlstrom L. Toft M. Taba P. Koks S. Hassin-Baer S. Majamaa K. Siitonen A. Tienari P. Okubadejo N.U. Ojo O.O. Shashkin C. Zharkinbekova N. Akhmetzhanov V. Kaishybayeva G. Karimova A. Khaibullin T. Lynch T.L. Hingorani A.D. Wood N.W.
December 2021Nature Research
Nature Communications
2021#12Issue 1
Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.
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Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, United Kingdom
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, WC1E 6BT, United Kingdom
University College London British Heart Foundation Research Accelerator Centre, New Delhi, India
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, CX Utrecht, 3584, Netherlands
Health Data Research UK, 222 Euston Road, London, United Kingdom
Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, QMUL, London, United Kingdom
Department of Molecular Neuroscience, UCL, London, United Kingdom
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Department of Clinical Neuroscience, University College London, London, United Kingdom
Biostatistics and Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff, United Kingdom
MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, United Kingdom
Institute of Healthy Ageing, Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
University of Reading, Reading, United Kingdom
University College London, London, United Kingdom
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom
UCL Institute of Neurology, London, United Kingdom
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom
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
UCL School of Pharmacy, London, United Kingdom
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
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, Centre d’Investigation Clinique Pitié Neurosciences CIC-1422, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
INSERM UMR 1220, Toulouse, France
Paul Sabatier University, Toulouse, France
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
DZNE, German Center for Neurodegenerative Diseases and Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tübingen, Germany
Department of Neurology, Ludwig-Maximilians-University Munich, München, Germany
Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
Inherited Movement Disorders Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
Neurogenomics Division, TGen, Phoenix, AZ, United States
Departments of Neurology, Neuroscience, and Molecular & 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
CEO/Consultant Data Tecnica International, Glen Echo, MD, United States
Baylor College of Medicine, Houston, TX, United States
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, United States
Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
National Institutes of Health, Bethesda, MD, United States
Departments of Neurology and Physiology, University of California, San Francisco, CA, United States
Gladstone Institute of Neurological Disease, San Francisco, CA, United States
Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, United States
Northwestern University Feinberg School of Medicine, Chicago, IL, United States
National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, United States
Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
Departments of Neuroscience & Clinical Genomics, Mayo Clinic, Jacksonville, FL, United States
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, Taub Institute for Research on Alzheimer’s Disease, New York, NY, United States
The Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, United States
Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, Department of Human Genetics, McGill University, Montréal, H3A 0G4, QC, Canada
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
Instituto de Biomedicina de Sevilla IBiS Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
Hospital Universitario Central de Asturias, Oviedo, Spain
Hospital Universitario San Cecilio de Granada, Universidad de Granada, Granada, Spain
Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Universidad de Murcia, Murcia, Spain
Hospital Clinic de Barcelona, Barcelona, Spain
Hospital General de Segovia, Segovia, Spain
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain
Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain
Departmento de Neurologia, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
Hospital Universitario Virgen de la Victoria, Malaga, Spain
Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Hospital Universitario Marqués de Valdecilla-IDIVAL and University of Cantabria, Santander, Spain
Hospital Universitario Ramón y Cajal, Madrid, Spain
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Department of Neurology, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain
Hospital Clinic Barcelona, Barcelona, Spain
Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain
Hospital Universitario Virgen de las Nieves, Granada, Instituto de Investigación Biosanitaria de, Granada, Spain
Department of Neurology, Hospital Universitario Infanta Sofía, Madrid, Spain
Hospital Universitario Donostia, Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain
Department of Neurology, Medical University of Vienna, Vienna, Austria
Department of Neurology, Oslo University Hospital, Oslo, Norway
Department of Neurology and Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway
Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Perth, 6150, WA, Australia
The Perron Institute for Neurological and Translational Science, Nedlands, Perth, 6009, WA, Australia
The Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, 5262101, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland
Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland
Clinical Neurosciences, Neurology, University of Helsinki, Helsinki, Finland
Helsinki University Hospital, Helsinki, Finland
University of Lagos, Lagos State, Nigeria
Kazakh National Medical University named after Asfendiyarov, Almaty, Kazakhstan
South Kazakhstan Medical Academy, Shymkent, Kazakhstan
Astana Medical University, Astana, Kazakhstan
Scientific and Practical Center “Institute of Neurology named after Smagul Kaishibayev”, Almaty, Kazakhstan
Semey Medical University, Semey, Kazakhstan
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland
Department of Clinical and Movement Neurosciences
Department of Medical Laboratory Technology
Laboratory of Neurogenetics
Institute of Cardiovascular Science
University College London British Heart Foundation Research Accelerator Centre
Department of Cardiology
Health Data Research UK
Preventive Neurology Unit
Department of Molecular Neuroscience
Department of Molecular Neuroscience
Institute of Translational Medicine
Department of Clinical Neuroscience
Biostatistics and Bioinformatics Unit
MRC Centre for Neuropsychiatric Genetics & Genomics
Institute of Healthy Ageing
University of Reading
University College London
MRC Centre for Neuropsychiatric Genetics and Genomics
UCL Institute of Neurology
MRC Centre for Neuropsychiatric Genetics and Genomics
Faculty of Medicine
University of Birmingham
Sandwell and West Birmingham Hospitals NHS Trust
UCL School of Pharmacy
Institut du Cerveau et de la Moelle épinière
Institut du Cerveau et de la Moelle épinière
INSERM UMR 1220
Paul Sabatier University
Department for Neurodegenerative Diseases
DZNE
DZNE
DZNE
Centre for Genetic Epidemiology
Department of Neurology
Department of Translational Genomics
Inherited Movement Disorders Unit
Department of Computer Science
Laboratory of Neurogenetics
Neurogenomics Division
Departments of Neurology
Jan and Dan Duncan Neurological Research Institute
CEO/Consultant Data Tecnica International
Baylor College of Medicine
Center for Neurodegenerative Science
Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics
National Institutes of Health
Departments of Neurology and Physiology
Gladstone Institute of Neurological Disease
Taube/Koret Center for Neurodegenerative Disease Research
Northwestern University Feinberg School of Medicine
National Institutes of Health Division of Clinical Research
Neurodegenerative Diseases Research Unit
Department of Neurology
Departments of Neuroscience & Clinical Genomics
Department of Neurology
The Aging Brain
Montreal Neurological Institute and Hospital
Department of Neurology
Instituto de Biomedicina de Sevilla IBiS Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit
Hospital Universitario Central de Asturias
Hospital Universitario San Cecilio de Granada
Instituto de Investigación Sanitaria Biodonostia
Universidad de Murcia
Hospital Clinic de Barcelona
Hospital General de Segovia
Memory Unit
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED)
Centro de Investigacion Biomedica
Hospital Universitario Virgen de las Nieves
Departmento de Neurologia
Instituto de Investigación Sanitaria Fundación Jiménez Díaz
Hospital Universitario Virgen de la Victoria
Hospital Universitario Marqués de Valdecilla-IDIVAL
Institut de Recerca Sant Joan de Déu
Hospital Universitario Marqués de Valdecilla-IDIVAL and University of Cantabria
Hospital Universitario Ramón y Cajal
Movement Disorders Unit
Department of Neurology
Hospital Clinic Barcelona
Instituto Ramón y Cajal de Investigación Sanitaria
Hospital Universitario Virgen de las Nieves
Department of Neurology
Hospital Universitario Donostia
Department of Neurology
Department of Neurology
Department of Neurology
Department of Neurology and Institute of Clinical Medicine
Department of Neurology and Neurosurgery
Centre for Molecular Medicine and Innovative Therapeutics
The Perron Institute for Neurological and Translational Science
The Movement Disorders Institute
Sackler Faculty of Medicine
Institute of Clinical Medicine
Department of Neurology and Medical Research Center
Clinical Neurosciences
Helsinki University Hospital
University of Lagos
Kazakh National Medical University named after Asfendiyarov
South Kazakhstan Medical Academy
Astana Medical University
Scientific and Practical Center “Institute of Neurology named after Smagul Kaishibayev”
Semey Medical University
School of Medicine and Medical Science
The Dublin Neurological Institute at the Mater Misericordiae University Hospital
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