Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome
Storm, Catherine S. ![Identificador ORCID](/img/uab/orcid.ico)
(University College London)
Kia, Demis A. (University College London)
Almramhi, Mona M. (King Abdulaziz University)
Bandres-Ciga, Sara ![Identificador ORCID](/img/uab/orcid.ico)
(National Institute on Aging (Estats Units d'Amèrica))
Finan, Chris (University Medical Center Utrecht)
Noyce, A. J. (UCL Institute of Neurology (Regne Unit))
Kaiyrzhanov, R. (UCL Institute of Neurology (Regne Unit))
Middlehurst, B. (University of Liverpool)
Tan, M. (University College London)
Houlden, Henry
(UCL Institute of Neurology (Regne Unit))
Morris, H. R. (University College London)
Plun-Favreau, H. (UCL Institute of Neurology (Regne Unit))
Holmans, Peter
(MRC Centre for Neuropsychiatric Genetics & Genomics)
Hardy, J. (UCL Institute of Neurology (Regne Unit))
Trabzuni, D. (UCL Institute of Neurology (Regne Unit))
Quinn, J. (Institute of Translational Medicine. University of Liverpool)
Bubb, Vivien (Institute of Translational Medicine. University of Liverpool)
Mok, K. Y. (UCL Institute of Neurology (Regne Unit))
Kinghorn, K. J. (University College London)
Lewis, P. (University of Reading)
Schreglmann, S. R. (UCL Institute of Neurology (Regne Unit))
Lovering, R. (University College London)
R'Bibo, L. (UCL Institute of Neurology (Regne Unit))
Manzoni, Claudia
(University of Reading)
Rizig, M. (UCL Institute of Neurology (Regne Unit))
Ryten, Mina (UCL Institute of Neurology (Regne Unit))
Guelfi, S. (UCL Institute of Neurology (Regne Unit))
Escott-Price, Valentina
(MRC Centre for Neuropsychiatric Genetics and Genomics. Cardiff University School of Medicine)
Chelban, Viorica
(UCL Institute of Neurology (Regne Unit))
Foltynie, T. (UCL Institute of Neurology (Regne Unit))
Williams, Nigel (MRC Centre for Neuropsychiatric Genetics and Genomics)
Morrison, K. E. (Faculty of Medicine. University of Southampton)
Clarke, C. (Sandwell and West Birmingham Hospitals NHS Trust)
Harvey, K. (UCL School of Pharmacy)
Jacobs, B. M. (Wolfson Institute of Preventive Medicine. QMUL)
Brice, Alexis
(Sorbonne Université)
Danjou, Fabrice
(Sorbonne Université)
Lesage, S. (Sorbonne Universités)
Corvol, Jean-Christophe
(Sorbonne Universités)
Martinez, M. (Paul Sabatier University)
Schulte, C. (DZNE. German Center for Neurodegenerative Diseases)
Brockmann, Kathrin
(DZNE. German Center for Neurodegenerative Diseases)
Simón-Sánchez, J. (DZNE. German Center for Neurodegenerative Diseases)
Heutink, Peter
(University of Tübingen)
Rizzu, P. (DZNE. German Center for Neurodegenerative Diseases)
Sharma, M. (University of Tubingen)
Gasser, T. (DZNE. German Center for Neurodegenerative Diseases)
Schneider, S. A. (udwig-Maximilians-University Munich)
Cookson, Mark R (Laboratory of Neurogenetics. National Institute on Aging)
Blauwendraat, Cornelis (Laboratory of Neurogenetics. National Institute on Aging)
Craig, David W
(University of Southern California)
Billingsley, K. (National Institute on Aging (Estats Units d'Amèrica))
Makarious, M. B. (National Institute on Aging (Estats Units d'Amèrica))
Narendra, D. P. (National Institute of Neurological Disorders and Stroke)
Faghri, Faraz (University of Illinois at Urbana-Champaign)
Gibbs, J. R. (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Hernandez, D. G. (National Institute on Aging (Estats Units d'Amèrica))
Van Keuren-Jensen, K. (Neurogenomics Division. TGen)
Shulman, J. M. (Texas Children's Hospital)
Iwaki, H. (Laboratory of Neurogenetics. National Institute on Aging)
Leonard, H. L. (Laboratory of Neurogenetics. National Institute on Aging)
Nalls, M. A. (CEO/Consultant Data Tecnica International)
Robak, L. (Baylor College of Medicine)
Bras, Jose
(Van Andel Research Institute)
Guerreiro, Rita
(Van Andel Research Institute)
Lubbe, S. (Northwestern University Feinberg School of Medicine)
Troycoco, T. (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Finkbeiner, S. (Taube/Koret Center for Neurodegenerative Disease Research)
Mencacci, N. E. (Northwestern University Feinberg School of Medicine)
Lungu, C. (National Institutes of Health Division of Clinical Research. NINDS. National Institutes of Health)
Singleton, A. B. (Laboratory of Neurogenetics. National Institute on Aging)
Scholz, S. W. (National Institute of Neurological Disorders and Stroke)
Reed, X. (Laboratory of Neurogenetics. National Institute on Aging)
Uitti, R. J. (Mayo Clinic)
Ross, O. A. (Mayo Clinic)
Grenn, F. P. (National Institute on Aging (Estats Units d'Amèrica))
Moore, A. (National Institute on Aging (Estats Units d'Amèrica))
Alcalay, Roy N (Columbia University Medical Center)
Wszolek, Z. K. (Mayo Clinic)
Gan-Or, Z. (McGill University)
Rouleau, G. A. (McGill University)
Krohn, L. (McGill University)
Mufti, K. (McGill University)
van Hilten, J. J. (Leiden University Medical Center)
Marinus, J. (Leiden University Medical Center)
Adarmes-Gómez, A.D
(Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Aguilar Barberà, Miquel (Mútua de Terrassa)
Alvarez, Ignacio
(Mútua de Terrassa)
Alvarez, Victoria
(Hospital Universitario Central de Asturias)
Barrero, F. J. (Universidad de Granada)
Yarza, Jesús Alberto Bergareche (Biodonostia Osasun Ikerketako Institutura (País Basc))
Bernal-Bernal, I. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Blázquez Estrada, Marta
(Hospital Universitario Central de Asturias)
Bonilla-Toribio, Marta (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Botía, J. A. (Universidad de Murcia)
Boungiorno, M. T. (Mútua de Terrassa)
Buiza-Rueda, Dolores
(Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Cámara, Ana
(Hospital Clínic i Provincial de Barcelona)
Carrillo, F. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Carrión-Claro, M. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Cerdan, Debora
(Hospital General de Segovia)
Clarimón, Jordi
(Institut d'Investigació Biomèdica Sant Pau)
Compta, Yaroslau
(Hospital Clínic i Provincial de Barcelona)
Diez-Fairen, M. (Mútua de Terrassa)
Dols Icardo, Oriol
(Institut d'Investigació Biomèdica Sant Pau)
Duarte, Jacinto (Hospital General de Segovia)
Duran, Raquel (Universidad de Granada)
Escamilla Sevilla, Francisco
(Instituto de Investigación Sanitaria de Granada)
Ezquerra, Mario
(Hospital Clínic i Provincial de Barcelona)
Feliz, Cici (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Fernández, Manel (Hospital Clínic i Provincial de Barcelona)
Fernández-Santiago, Rubén
(Hospital Clínic i Provincial de Barcelona)
Garcia, C.. (Hospital Universitario Central de Asturias)
García-Ruiz, Pedro (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Gómez-Garre, Pilar
(Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Gomez Heredia, Maria Jose (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Gonzalez-Aramburu, Isabel
(Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Gorostidi Pagola, Ana (Biodonostia Osasun Ikerketako Institutura (País Basc))
Hoenicka, Janet
(Institut de Recerca Sant Joan de Déu)
Infante, Jon
(Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Jesús, S. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Jiménez-Escrig, Adriano
(Hospital Universitario Ramón y Cajal (Madrid))
Kulisevsky, Jaime
(Institut d'Investigació Biomèdica Sant Pau)
Labrador-Espinosa, Miguel A
(Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Lopez-Sendon, Jose Luis (Hospital Universitario Ramón y Cajal (Madrid))
de Munain Arregui, A. L. (Biodonostia Osasun Ikerketako Institutura (País Basc))
Macías-García, Daniel
(Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Torres, I. M. (Hospital Universitari i Politècnic La Fe (València))
Marín, Juan (Institut d'Investigació Biomèdica Sant Pau)
Marti, Maria Jose (Hospital Clínic i Provincial de Barcelona)
Martínez-Castrillo, Juan Carlos
(Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Méndez-del-Barrio, C. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
González, M. M. (Hospital Universitario Central de Asturias)
Mata, Marina
(Hospital Universitario Virgen de las Nieves (Granada))
Mínguez, A. (Hospital Universitario Virgen de las Nieves (Granada))
Mir, P. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Rezola, E. M. (Biodonostia Osasun Ikerketako Institutura (País Basc))
Muñoz, Esteban (Hospital Clínic i Provincial de Barcelona)
Pagonabarraga Mora, Javier
(Hospital Universitario Infanta Sofía (San Sebastián de los Reyes))
Pastor, Pau
(Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Perez-Errazquin, Francisco (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Periñán-Tocino, T. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Ruiz-Martínez, J. (Biodonostia Osasun Ikerketako Institutura (País Basc))
Ruz, Clara (Universidad de Granada)
Rodriguez, A. S. (Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Sierra, Maria (Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Suarez-Sanmartin, E. (Hospital Universitario Central de Asturias)
Tabernero, Cesar (Hospital General de Segovia)
Tartari, J. P. (Mútua de Terrassa)
Tejera-Parrado, C. (v)
Tolosa, Eduard
(Hospital Clínic i Provincial de Barcelona)
Valldeoriola, Francesc
(Hospital Clínic i Provincial de Barcelona)
Vargas-González, L. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Vela, Lydia
(Hospital Universitario Fundación Alcorcón)
Vives, Francisco (Universidad de Granada)
Zimprich, Alexander (Medical University of Vienna)
Pihlstrom, L. (Oslo University Hospital (Oslo, Noruega))
Toft, M. (Oslo University Hospital (Oslo, Noruega))
Taba, Pille
(University of Tartu)
Koks, S. (The Perron Institute for Neurological and Translational Science)
Hassin-Baer, S. (Sackler Faculty of Medicine. Tel Aviv University)
Majamaa, K. (Oulu University Hospital (Finlàndia))
Siitonen, A. (Oulu University Hospital (Finlàndia))
Tienari, P. (Helsinki University Hospital (Finlàndia))
Okubadejo, N. U. (University of Lagos)
Ojo, O. O. (University of Lagos)
Shashkin, C. (Kazakh National Medical University named after Asfendiyarov)
Zharkinbekova, N. (South Kazakhstan Medical Academy)
Akhmetzhanov, Vadim (Astana Medical University)
Kaishybayeva, G. (Scientific and Practical Center "Institute of Neurology named after Smagul Kaishibayev")
Karimova, A. (Scientific and Practical Center "Institute of Neurology named after Smagul Kaishibayev")
Khaibullin, T. (Semey Medical University)
Lynch, T. L. (The Dublin Neurological Institute at the Mater Misericordiae University Hospital)
Hingorani, Aroon
(Health Data Research UK)
Wood, Nicholas W..
(University College London)
Universitat Autònoma de Barcelona
Fecha: |
2021 |
Resumen: |
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. |
Derechos: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. ![Creative Commons](/img/licenses/by.ico) |
Lengua: |
Anglès |
Documento: |
Article ; recerca ; Versió publicada |
Materia: |
Brain ;
Case-Control Studies ;
Cohort Studies ;
Disease Progression ;
Gene Expression Regulation ;
Genetic Predisposition to Disease ;
Genetic Variation ;
Genome, Human ;
Humans ;
Mendelian Randomization Analysis ;
Parkinson Disease ;
Quantitative Trait Loci ;
Risk Factors |
Publicado en: |
Nature communications, Vol. 12 Núm. 1 (december 2021) , p. 7342, ISSN 2041-1723 |
DOI: 10.1038/s41467-021-26280-1
PMID: 34930919
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Registro creado el 2022-07-26, última modificación el 2024-08-06