Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
Catherine S. Storm(National Hospital for Neurology and Neurosurgery), Demis A. Kia(National Hospital for Neurology and Neurosurgery), Mona Mohammad Almramhi(King Abdulaziz University), Sara Bandrés‐Ciga(National Institute on Aging), Chris Finan(Heidelberg University), Alastair J. Noyce(University College London), Rauan Kaiyrzhanov(University College London), Ben Middlehurst(University of Liverpool), Manuela Tan(University College London), Henry Houlden(University College London), Huw R. Morris(University College London), Hélène Plun‐Favreau(University College London), Peter Holmans(Cardiff University), John Hardy(University College London), Daniah Trabzuni(University College London), John P. Quinn(University of Liverpool), Vivien J. Bubb(University of Liverpool), Kin Y. Mok(University College London), Kerri J. Kinghorn(University College London), Patrick A. Lewis(University of Reading), Sebastian R. Schreglmann(University College London), Ruth C. Lovering(University College London), Lea R’Bibo(University College London), Claudia Manzoni(University of Reading), Mie Rizig(University College London), Mina Ryten(University College London), Sebastian Guelfi(University College London), Valentina Escott‐Price(Cardiff University), Viorica Chelban(University College London), Thomas Foltynie(University College London), Nigel Williams(Genomics (United Kingdom)), Karen Morrison(University of Southampton), Carl E Clarke(Sandwell & West Birmingham Hospitals NHS Trust), Kirsten Harvey(The London College), Benjamin M. Jacobs, Alexis Brice(Centre National de la Recherche Scientifique), Fabrice Danjou(Centre National de la Recherche Scientifique), Suzanne Lesage(Centre National de la Recherche Scientifique), Jean‐Christophe Corvol(Centre National de la Recherche Scientifique), María Martínez(Université Toulouse III - Paul Sabatier), Claudia Schulte(German Center for Neurodegenerative Diseases), Kathrin Brockmann(German Center for Neurodegenerative Diseases), Javier Simón‐Sánchez(German Center for Neurodegenerative Diseases), Peter Heutink(German Center for Neurodegenerative Diseases), Patrizia Rizzu(German Center for Neurodegenerative Diseases), Manu Sharma(University of Tübingen), Thomas Gasser(German Center for Neurodegenerative Diseases), Susanne A. Schneider(Ludwig-Maximilians-Universität München), Mark Cookson(National Institute on Aging), Cornelis Blauwendraat(National Institute on Aging), David W. Craig(University of Southern California), Kimberley J. Billingsley(National Institute on Aging), Mary B. Makarious(National Institute on Aging), Derek P. Narendra(National Institute of Neurological Disorders and Stroke), Faraz Faghri(University of Illinois Urbana-Champaign), J. Raphael Gibbs(National Institutes of Health), Dena Hernández(National Institute on Aging), Kendall Van Keuren‐Jensen(Translational Genomics Research Institute), Joshua Shulman(Baylor College of Medicine), Hirotaka Iwaki(National Institute on Aging), Hampton L. Leonard(National Institute on Aging), Mike A. Nalls(Data Tecnica International (United States)), Laurie Robak(Baylor College of Medicine), José Brás(Van Andel Institute), Rita Guerreiro(Van Andel Institute), Steven Lubbe(Northwestern University), Timothy Troycoco(National Institutes of Health), Steven Finkbeiner(Gladstone Institutes), Niccolò E. Mencacci(Northwestern University), Codrin Lungu(National Institutes of Health), Andrew Singleton(National Institute on Aging), Sonja W. Scholz(National Institute of Neurological Disorders and Stroke), Xylena Reed(National Institute on Aging), Ryan J. Uitti(WinnMed), Owen A. Ross(Mayo Clinic in Florida), Francis P. Grenn(National Institute on Aging), Anni Moore(National Institute on Aging), Roy N. Alcalay(Columbia University Irving Medical Center), Zbigniew K. Wszołek(WinnMed), Ziv Gan‐Or(Montreal Neurological Institute and Hospital), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Lynne Krohn(Montreal Neurological Institute and Hospital), Kheireddin Mufti(Montreal Neurological Institute and Hospital), Jacobus J. van Hilten(Leiden University Medical Center), Johan Marinus(Leiden University Medical Center), Astrid D. Adarmes-Gómez(Instituto de Biomedicina de Sevilla), Miquel Aguilar(University Hospital Mútua de Terrassa), Ignacio Álvarez(University Hospital Mútua de Terrassa), Victoria Álvarez(Hospital Universitario Central de Asturias), Francisco Javier Barrero(Universidad de Granada), Jesús Alberto Bergareche Yarza(Biogipuzkoa Health Research Institute), Inmaculada Bernal‐Bernal(Instituto de Biomedicina de Sevilla), Marta Blázquez Estrada(Hospital Universitario Central de Asturias), Marta Bonilla‐Toribio(Instituto de Biomedicina de Sevilla), Juan A. Botía(Universidad de Murcia), María Teresa Boungiorno(University Hospital Mútua de Terrassa), Dolores Buiza‐Rueda(Instituto de Biomedicina de Sevilla), Ana Cámara(Hospital Clínic de Barcelona), Fátima Carrillo(Instituto de Biomedicina de Sevilla), Mario Carrión‐Claro(Instituto de Biomedicina de Sevilla), Debora Cerdan(Hospital General De Segovia), Jordi Clarimón(Universitat Autònoma de Barcelona), Yaroslau Compta(Hospital Clínic de Barcelona), Mónica Díez-Fairén(University Hospital Mútua de Terrassa), Oriol Dols‐Icardo(Universitat Autònoma de Barcelona), Jacinto Duarte(Hospital General De Segovia), Raquel Durán(Universidad de Granada), Francisco Escamilla‐Sevilla(Instituto de Investigación Biosanitaria de Granada), Mario Ezquerra(Hospital Clínic de Barcelona), Cici Feliz(Hospital Universitario Fundación Jiménez Díaz), Manel Fernández(Hospital Clínic de Barcelona), Rubén Fernández‐Santiago(Hospital Clínic de Barcelona), Ciara García(Hospital Universitario Central de Asturias), Pedro Ruiz(Hospital Universitario Fundación Jiménez Díaz), Pilar Gómez‐Garre(Instituto de Biomedicina de Sevilla), María José Gómez Heredia(Hospital Clínico Universitario Virgen de la Victoria), Isabel González Aramburu(Instituto de Investigación Marqués de Valdecilla), Ana Gorostidi Pagola(Biogipuzkoa Health Research Institute), Janet Hoenicka(Institut de Recerca Sant Joan de Déu), Jon Infante(Universidad de Cantabria), Silvia Jesús(Instituto de Biomedicina de Sevilla), Adriano Jiménez‐Escrig(Hospital Universitario Ramón y Cajal), Jaime Kulisevsky(Universitat Autònoma de Barcelona), Miguel A. Labrador‐Espinosa(Instituto de Biomedicina de Sevilla), José Luis López-Sendón(Hospital Universitario Ramón y Cajal), Adolfo López de Munaín Arregui(Biogipuzkoa Health Research Institute), Daniel Macías(Instituto de Biomedicina de Sevilla), Irene Martínez‐Torres(Instituto de Investigación Sanitaria La Fe), Juan Marín‐Lahoz(Universitat Autònoma de Barcelona), Marı́a José Martı́(Hospital Clínic de Barcelona), Juan Carlos Martínez‐Castrillo(Instituto Ramón y Cajal de Investigación Sanitaria), Carlota Méndez‐del‐Barrio(Instituto de Biomedicina de Sevilla), Manuel Menéndez‐González(Hospital Universitario Central de Asturias), Marina Mata(Instituto de Investigación Biosanitaria de Granada), Adolfo Mínguez‐Castellanos(Instituto de Investigación Biosanitaria de Granada), Pablo Mir(Instituto de Biomedicina de Sevilla), Elisabet Mondragón Rezola(Biogipuzkoa Health Research Institute), Esteban Muñoz(Hospital Clínic de Barcelona), Javier Pagonabarraga(Universitat Autònoma de Barcelona), Pau Pástor(University Hospital Mútua de Terrassa), Francisco Pérez Errazquin(Hospital Clínico Universitario Virgen de la Victoria), María Teresa Periñán(Instituto de Biomedicina de Sevilla), Javier Ruiz‐Martínez(Biogipuzkoa Health Research Institute), Clara Ruz(Universidad de Granada), A Rodríguez(Instituto de Investigación Marqués de Valdecilla), María Sierra(Instituto de Investigación Marqués de Valdecilla), Esther Suárez-Sanmartín(Hospital Universitario Central de Asturias), César Tabernero(Hospital General De Segovia), Juan Pablo Tartari(University Hospital Mútua de Terrassa), Cristina Tejera‐Parrado(Instituto de Biomedicina de Sevilla), Eduard Tolosa(Hospital Clínic de Barcelona), Francesc Valldeoriola(Hospital Clínic de Barcelona), Laura Vargas‐González(Instituto de Biomedicina de Sevilla), Lydia Vela(Hospital Universitario Fundación Alcorcón), Francisco Vives(Universidad de Granada), Alexander Zimprich(Medical University of Vienna), Lasse Pihlstrøm(Oslo University Hospital), Mathias Toft(Oslo University Hospital), Pille Taba(University of Tartu), Sulev Kõks(Murdoch University), Sharon Hassin‐Baer(Tel Aviv University), Kari Majamaa(Oulu University Hospital), Ari Siitonen(Oulu University Hospital), Pentti Tienari(University of Helsinki), Njideka Okubadejo(University of Lagos), Oluwadamilola O. Ojo(University of Lagos), Chingiz Shashkin(Kazakh National Medical University), Nazira Zharkinbekova(South Kazakhstan Medical Academy), Vadim Akhmetzhanov(Astana Medical University), Gulnaz Kaishybayeva, Altynay Karimova, Хайбуллин Т.Н.(Semey Medical University), Timothy Lynch(University College Dublin), Aroon D. Hingorani(Health Data Research UK), Nicholas Wood(Queen Mary University of London)
Cited by 213Open Access
Abstract
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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