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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
Nature Communications, Volume 12, No. 1, Article 7342, Year 2021
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Description
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. © 2021, The Author(s).
Authors & Co-Authors
Storm, Catherine S.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Kia, Demis A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Almramhi, Mona Mohammad
United Kingdom, London
Ucl Queen Square Institute of Neurology
Saudi Arabia, Jeddah
King Abdulaziz University
Bandres-Ciga, Sara
United States, Bethesda
National Institute on Aging Nia
Finan, Chris I.
United Kingdom, London
University College London
India, New Delhi
University College London British Heart Foundation Research Accelerator Centre
Netherlands, Utrecht
University Medical Center Utrecht
Noyce, Alastair John
United Kingdom, London
Queen Mary University of London
United Kingdom, London
University College London
Kaiyrzhanov, Rauan
United Kingdom, London
Ucl Queen Square Institute of Neurology
Middlehurst, Ben
United Kingdom, Liverpool
University of Liverpool
Tan, Manuela M.X.
United Kingdom, London
University College London
Houlden, Henry H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Morris, Huw R.
United Kingdom, London
University College London
Plun-Favreau, Hélène
United Kingdom, London
Ucl Queen Square Institute of Neurology
Holmans, Peter A.
United Kingdom, Cardiff
Institute of Psychological Medicine and Clinical Neurosciences
United Kingdom, Cardiff
Mrc Centre for Neuropsychiatric Genetics and Genomics
Hardy, John A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Trabzuni, Daniah
United Kingdom, London
Ucl Queen Square Institute of Neurology
Quinn, John P.
United Kingdom, Liverpool
University of Liverpool
Bubb, Vivien Jill
United Kingdom, Liverpool
University of Liverpool
Mok, Kin Y.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Kinghorn, Kerri J.
United Kingdom, London
University College London
Lewis, Patrick Alfryn
United Kingdom, Reading
University of Reading
Schreglmann, Sebastian R.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Lovering, Ruth C.
United Kingdom, London
University College London
R’Bibo, Lea
United Kingdom, London
Ucl Queen Square Institute of Neurology
Manzoni, Claudia
United Kingdom, Reading
University of Reading
Rizig, Mie A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Ryten, Mina
United Kingdom, London
Ucl Queen Square Institute of Neurology
Guelfi, Sebastian
United Kingdom, London
Ucl Queen Square Institute of Neurology
Escott-Price, Valentina
United Kingdom, Cardiff
Mrc Centre for Neuropsychiatric Genetics and Genomics
Chelban, Viorica
United Kingdom, London
Ucl Queen Square Institute of Neurology
Foltynie, Thomas
United Kingdom, London
Ucl Queen Square Institute of Neurology
Williams, Nigel M.
United Kingdom, Cardiff
Mrc Centre for Neuropsychiatric Genetics and Genomics
Morrison, Karen E.
United Kingdom, Southampton
University of Southampton
Clarke, Carl E.
United Kingdom, Birmingham
University of Birmingham
United Kingdom, West Bromwich
Sandwell and West Birmingham Hospitals Nhs Trust
Harvey, Kirsten
United Kingdom, London
Ucl School of Pharmacy
Jacobs, Benjamin Meir
United Kingdom, London
Queen Mary University of London
Brice, Alexis
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Danjou, Fabrice
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Lesage, Suzanne
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Corvol, Jean Christophe
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Martinez, Maria M.
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Toulouse
Université Toulouse Iii - Paul Sabatier
Schulte, Claudia M.S.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Brockmann, Kathrin
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Simón-Sánchez, Javier
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Heutink, Peter
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Rizzu, Patrizia
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Sharma, Manu
Germany, Tubingen
Eberhard Karls Universität Tübingen
Gasser, Thomas
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Schneider, Susanne Annika
Germany, Munich
Ludwig-maximilians-universität München
Cookson, Mark Robert
United States, Bethesda
National Institute on Aging Nia
Blauwendraat, Cornelis
United States, Bethesda
National Institute on Aging Nia
Craig, David Wesley
United States, Los Angeles
University of Southern California
Billingsley, Kimberley J.
United States, Bethesda
National Institute on Aging Nia
Makarious, Mary B.
United States, Bethesda
National Institute on Aging Nia
Narendra, Derek P.
United States, Bethesda
National Institute of Neurological Disorders and Stroke
Faghri, Faraz
United States, Bethesda
National Institute on Aging Nia
United States, Urbana
University of Illinois Urbana-champaign
Gibbs, J. Raphael
United States, Bethesda
National Institutes of Health Nih
Hernandez, Dena G.
United States, Bethesda
National Institute on Aging Nia
Van Keuren-Jensen, Kendall R.
United States, Phoenix
Translational Genomics Research Institute
Shulman, Joshua M.
United States, Houston
Baylor College of Medicine
United States, Houston
Texas Children's Hospital
Iwaki, Hirotaka
United States, Bethesda
National Institute on Aging Nia
Leonard, Hampton L.
United States, Bethesda
National Institute on Aging Nia
Nalls, Mike A.
United States, Bethesda
National Institute on Aging Nia
United States, Glen Echo
Data Tecnica International
Robak, Laurie A.
United States, Houston
Baylor College of Medicine
Brás, José Miguel
United States, Grand Rapids
Van Andel Research Institute
Guerreiro, Rita João
United States, Grand Rapids
Van Andel Research Institute
Lubbe, Steven J.
United States, Chicago
Northwestern University Feinberg School of Medicine
Troycoco, Timothy
United States, Bethesda
National Institutes of Health Nih
Finkbeiner, Steven M.
United States, San Francisco
University of California, San Francisco
United States, San Francisco
Gladstone Institute of Neurological Disease
United States, San Francisco
Taube/koret Center for Neurodegenerative Disease Research
Mencacci, Niccolò Emanuele
United States, Chicago
Northwestern University Feinberg School of Medicine
Lungu, Codrin I.
United States, Bethesda
National Institutes of Health Nih
Singleton, Andrew B.
United States, Bethesda
National Institute on Aging Nia
Scholz, Sonja W.
United States, Bethesda
National Institute of Neurological Disorders and Stroke
Reed, Xylena
United States, Bethesda
National Institute on Aging Nia
Uitti, Ryan J.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Ross, Owen A.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Grenn, Francis P.
United States, Bethesda
National Institute on Aging Nia
Moore, Anni K.
United States, Bethesda
National Institute on Aging Nia
Alcalay, Roy N.
United States, New York
Columbia University Irving Medical Center
Wszołek, Zbigniew K.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Gan-Or, Ziv
Canada, Montreal
Mcgill Faculty of Medicine and Health Sciences
Rouleau, Guy Armand
Canada, Montreal
Mcgill Faculty of Medicine and Health Sciences
Krohn, Lynne
Canada, Montreal
Mcgill Faculty of Medicine and Health Sciences
Mufti, Kheireddin
Canada, Montreal
Mcgill Faculty of Medicine and Health Sciences
van Hilten, Jacobus Johannes Bob
Netherlands, Leiden
Leids Universitair Medisch Centrum
Marinus, Johan
Netherlands, Leiden
Leids Universitair Medisch Centrum
Adarmes-GɃmez, Astrid D.
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Aguilar, Miquel Chávez
Spain, Terrassa
Mutua de Terrassa
Alvarez, Ignacio
Spain, Terrassa
Mutua de Terrassa
Alvarez, Victoria
Spain, Oviedo
Hospital Universitario Central de Asturias
Barrero, Francisco Javier
Spain, Granada
Universidad de Granada
Yarza, Jesús Alberto Bergareche
Spain, Donostia-san Sebastian
Biodonostia Health Research Institute
Bernal-Bernal, Inmaculada
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Blázquez Estrada, Marta
Spain, Oviedo
Hospital Universitario Central de Asturias
Bonilla-Toribio, Marta
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Botia, Juan A.
Spain, Murcia
Universidad de Murcia
Boungiorno, María Teresa
Spain, Terrassa
Mutua de Terrassa
Buiza-Rueda, Dolores
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Cámara, Ana
Spain, Barcelona
Hospital Clinic Barcelona
Carrillo, Fátima
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Carrion-Claro, Mario
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Cerdán, Débora María
Spain, Segovia
Hospital General de Segovia
Clarimón, Jordi
Spain, Barcelona
Institut de Recerca Sant Pau ir Sant Pau
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Compta, Yaroslau
Spain, Barcelona
Hospital Clinic Barcelona
Diez-Fairen, Monica
Spain, Terrassa
Mutua de Terrassa
Dols-Icardo, Oriol
Spain, Barcelona
Institut de Recerca Sant Pau ir Sant Pau
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Duarte, Jacinto
Spain, Segovia
Hospital General de Segovia
Duran, R. L.
Spain, Granada
Universidad de Granada
Escamilla, Francisco
Spain, Granada
Complejo Hospitalario Universitario de Granada
Ezquerra, Mario
Spain, Barcelona
Hospital Clinic Barcelona
Feliz, Cici E.
Spain, Madrid
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Fernández-Martínez, Manuel Jesús
Spain, Barcelona
Hospital Clinic Barcelona
Fernández-Santiago, Rubén
Spain, Barcelona
Hospital Clinic Barcelona
Garcia, Ciara
Spain, Oviedo
Hospital Universitario Central de Asturias
García-Ruiz, Pedro J.
Spain, Madrid
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Gómez-Garre, Pilar
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Heredia, María José Gómez
Spain, Malaga
Hospital Universitari Virgen de la Victoria
González-Aramburu, Isabel
Spain, Santander
Hospital Universitario Marqués de Valdecilla
Pagola, Ana Gorostidi
Spain, Donostia-san Sebastian
Biodonostia Health Research Institute
Infante-Ceberio, Jon
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Spain, Santander
Universidad de Cantabria
Jesús, Silvia
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Labrador-Espinosa, Miguel A.
Spain, Madrid
Consejo Superior de Investigaciones Científicas
López-Sendón, José Luís
Spain, Madrid
Hospital Universitario Ramón y Cajal
de Munain Arregui, Adolfo López
Spain, Donostia-san Sebastian
Biodonostia Health Research Institute
Macías, Daniel
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Martí, María José
Spain, Barcelona
Hospital Clinic Barcelona
Méndez-Del-Barrio, Carlota
Spain, Madrid
Consejo Superior de Investigaciones Científicas
González, Manuel Menéndez
Spain, Oviedo
Hospital Universitario Central de Asturias
Mir, Pablo
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Rezola, Elisabet Mondragón
Spain, Donostia-san Sebastian
Biodonostia Health Research Institute
Pástor, Pau
Spain, Terrassa
Mutua de Terrassa
Periñan, Maria Teresa
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Ruíz-Martínez, Javier
Spain, Donostia-san Sebastian
Biodonostia Health Research Institute
Suarez-Sanmartin, Esther
Spain, Oviedo
Hospital Universitario Central de Asturias
Tartari, Juan Pablo
Spain, Terrassa
Mutua de Terrassa
Tejera-Parrado, Cristina
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Tolosa, Eduardo S.
Spain, Barcelona
Hospital Clinic Barcelona
Vargas-González, Laura
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Vives, F.
Spain, Granada
Universidad de Granada
Zimprich, Alexander
Austria, Vienna
Medizinische Universität Wien
Pihlstrom, Lasse
Norway, Oslo
Oslo Universitetssykehus
Toft, Mathias
Norway, Oslo
Oslo Universitetssykehus
Taba, Pille
Estonia, Tartu
Tartu Ülikool
Kõks, Sulev V.
Australia, Perth
Murdoch University
Australia, Perth
Perron Institute for Neurological and Translational Science
Hassin-Baer, Sharon
Israel, Tel Hashomer Tel Aviv
Chaim Sheba Medical Center Israel
Israel, Tel Aviv-yafo
Tel Aviv University
Okubadejo, Njideka U.
Nigeria, Lagos
University of Lagos
Ojo, Oluwadamilola Omolara
Nigeria, Lagos
University of Lagos
Shashkin, Chingiz
Kazakhstan, Almaty
Asfendiyarov Kazakh National Medical University
Zharkinbekova, N. A.
Kazakhstan, Shymkent
South Kazakhstan Medical Academy
Lynch, Timothy L.
Ireland, Dublin
University College Dublin
Ireland, Dublin
Mater Misericordiae University Hospital
Hingorani, Aroon Dinesh
United Kingdom, London
University College London
India, New Delhi
University College London British Heart Foundation Research Accelerator Centre
United Kingdom, London
Health Data Research uk
Wood, Nick William
United Kingdom, London
Ucl Queen Square Institute of Neurology
Statistics
Citations: 41
Authors: 151
Affiliations: 78
Identifiers
Doi:
10.1038/s41467-021-26280-1
ISSN:
20411723
Research Areas
Genetics And Genomics
Study Design
Randomised Control Trial
Cohort Study
Study Approach
Quantitative