Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
Authors: Storm Catherine S. , Kia Demis A. , Almramhi Mona M. , Bandres-Ciga Sara , Finan Chris ,   International Parkinson’s Disease Genomics Consortium (IPDGC), Noyce Alastair J. , Kaiyrzhanov Rauan , Middlehurst Ben , Tan Manuela , Houlden Henry , Morris Huw R. , Plun-Favreau Helene , Holmans Peter , Hardy John , Trabzuni Daniah , Quinn John , Bubb Vivien , Mok Kin Y. , Kinghorn Kerri J. , Lewis Patrick , Schreglmann Sebastian R. , Lovering Ruth , R’Bibo Lea , Manzoni Claudia , Rizig Mie , Ryten Mina , Guelfi Sebastian , Escott-Price Valentina , Chelban Viorica , Foltynie Thomas , Williams Nigel , Morrison Karen E. , Clarke Carl , Harvey Kirsten , Jacobs Benjamin M. , Brice Alexis , Danjou Fabrice , Lesage Suzanne , Corvol Jean-Christophe , Martinez Maria , Schulte Claudia , Brockmann Kathrin , Simón-Sánchez Javier , Heutink Peter , Rizzu Patrizia , Sharma Manu , Gasser Thomas , Schneider Susanne A. , Cookson Mark R. , Blauwendraat Cornelis , Craig David W. , Billingsley Kimberley , Makarious Mary B. , Narendra Derek P. , Faghri Faraz , Gibbs J. Raphael , Hernandez Dena G. , Van Keuren-Jensen Kendall , Shulman Joshua M. , Iwaki Hirotaka , Leonard Hampton L. , Nalls Mike A. , Robak Laurie , Bras Jose , Guerreiro Rita , Lubbe Steven , Troycoco Timothy , Finkbeiner Steven , Mencacci Niccolo E. , Lungu Codrin , Singleton Andrew B. , Scholz Sonja W. , Reed Xylena , Uitti Ryan J. , Ross Owen A. , Grenn Francis P. , Moore Anni , Alcalay Roy N. , Wszolek Zbigniew K. , Gan-Or Ziv , Rouleau Guy A. , Krohn Lynne , Mufti Kheireddin , van Hilten Jacobus J. , Marinus Johan , Adarmes-Gómez Astrid D. , Aguilar Miquel , Alvarez Ignacio , Alvarez Victoria , Barrero Francisco Javier , Yarza Jesús Alberto Bergareche , Bernal-Bernal Inmaculada , Blazquez Marta , Bonilla-Toribio Marta , Botía Juan A. , Boungiorno María Teresa , Buiza-Rueda Dolores , Cámara Ana , Carrillo Fátima , Carrión-Claro Mario , Cerdan Debora , Clarimón Jordi , Compta Yaroslau , Diez-Fairen Monica , Dols-Icardo Oriol , Duarte Jacinto , Duran Raquel , Escamilla-Sevilla Francisco , Ezquerra Mario , Feliz Cici , Fernández Manel , Fernández-Santiago Rubén , Garcia Ciara , García-Ruiz Pedro , Gómez-Garre Pilar , Heredia Maria Jose Gomez , Gonzalez-Aramburu Isabel , Pagola Ana Gorostidi , Hoenicka Janet , Infante Jon , Jesús Silvia , Jimenez-Escrig Adriano , Kulisevsky Jaime , Labrador-Espinosa Miguel A. , Lopez-Sendon Jose Luis , de Munain Arregui Adolfo López , Macias Daniel , Torres Irene Martínez , Marín Juan , Marti Maria Jose , Martínez-Castrillo Juan Carlos , Méndez-del-Barrio Carlota , González Manuel Menéndez , Mata Marina , Mínguez Adolfo , Mir Pablo , Rezola Elisabet Mondragon , Muñoz Esteban , Pagonabarraga Javier , Pastor Pau , Errazquin Francisco Perez , Periñán-Tocino Teresa , Ruiz-Martínez Javier , Ruz Clara , Rodriguez Antonio Sanchez , Sierra María , Suarez-Sanmartin Esther , Tabernero Cesar , Tartari Juan Pablo , Tejera-Parrado Cristina , Tolosa Eduard , Valldeoriola Francesc , Vargas-González Laura , Vela Lydia , Vives Francisco , Zimprich Alexander , Pihlstrom Lasse , Toft Mathias , Taba Pille , Koks Sulev , Hassin-Baer Sharon , Majamaa Kari , Siitonen Ari , Tienari Pentti , Okubadejo Njideka U. , Ojo Oluwadamilola O. , Shashkin Chingiz , Zharkinbekova Nazira , Akhmetzhanov Vadim , Kaishybayeva Gulnaz , Karimova Altynay , Khaibullin Talgat , Lynch Timothy L. , Hingorani Aroon D. , Wood Nicholas W. 
Published: December 2021

AbstractParkinson’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.