Finding genetically-supported drug targets for Parkinson\u2019s disease using Mendelian randomization of the druggable genome

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

doi:10.1038/s41467-021-26280-1

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.

Highlights

Parkinson’s disease is a neurodegenerative movement disorder that currently has no diseasemodifying treatment, partly owing to inefficiencies in drug target identification and validation
Incorporating genetics in drug development could be one of the most efficient ways to improve the process, because drugs with genetic support are considerably more likely to succeed in clinical trials[4,5,6]
We kept eQTLs with false discovery rate (FDR) < 0.05 and located within 5 kb of the associated gene to increase the specificity of the eQTL

Summary

Introduction

Parkinson’s disease is a neurodegenerative movement disorder that currently has no diseasemodifying 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. SNPs associated with expression levels of a gene (expression quantitative trait loci, eQTLs) may be analogous to lifelong exposure to a medication targeting the encoded protein[8,16]. We use eQTLs in blood and brain tissue to predict the efficacy of over 3000 drug-targeting mechanisms in two independent PD case-control cohorts and examine several PD progression markers (Fig. 1c). Using large-scale, openly available data and MR techniques, we propose a list of genetically-supported drug targets for PD, including repurposing opportunities of alreadylicensed or clinical-phase drugs

Methods

Results

Conclusion