Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
Catherine S. Storm, Demis A. Kia, Mona Mohammad Almramhi, Sara Bandrés‐Ciga, Chris Finan, Alastair J. Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Manuela Tan, Henry Houlden, Huw R. Morris, Hélène Plun‐Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, John P. Quinn, Vivien J. Bubb, Kin Y. Mok, Kerri J. Kinghorn, Patrick A. Lewis, Sebastian R. Schreglmann, Ruth C. Lovering, Lea R’Bibo, Claudia Manzoni, Mie Rizig, Mina Ryten, Sebastian Guelfi, Valentina Escott‐Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Karen Morrison, Carl E Clarke, Kirsten Harvey, Benjamin M. Jacobs, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean‐Christophe Corvol, María Martínez, Claudia Schulte, Kathrin Brockmann, Javier Simón‐Sánchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Susanne A. Schneider, Mark Cookson, Cornelis Blauwendraat, David W. Craig, Kimberley J. Billingsley, Mary B. Makarious, Derek P. Narendra, Faraz Faghri, J. Raphael Gibbs, Dena Hernández, Kendall Van Keuren‐Jensen, Joshua Shulman, Hirotaka Iwaki, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, José Brás, Rita Guerreiro, Steven Lubbe, Timothy Troycoco, Steven Finkbeiner, Niccolò E. Mencacci, Codrin Lungu, Andrew Singleton, Sonja W. Scholz, Xylena Reed, Ryan J. Uitti, Owen A. Ross, Francis P. Grenn, Anni Moore, Roy N. Alcalay, Zbigniew K. Wszołek, Ziv Gan‐Or, Guy A. Rouleau, Lynne Krohn, Kheireddin Mufti, Jacobus J. van Hilten, Johan Marinus, Astrid D. Adarmes-Gómez, Miquel Aguilar, Ignacio Álvarez, Victoria Álvarez, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal‐Bernal, Marta Blázquez Estrada, Marta Bonilla‐Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza‐Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión‐Claro
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.