Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome
Por:
Storm, CS, Kia, DA, Almramhi, MM, Bandres-Ciga, S, Finan, C, Hingorani, AD, Wood, NW, Clarimón, J., Dols-Icardo O., Kulisevsky J., Marín J., Pagonabarraga J., Lynch, Timothy L.
Publicada:
20 dic 2021
Resumen:
There is currently no disease-modifying treatment for Parkinson's disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson's disease using Mendelian randomization of the druggable genome.
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.
Filiaciones:
Storm, CS:
UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England
Kia, DA:
UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England
Almramhi, MM:
UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England
King Abdulaziz Univ, Fac Appl Med Sci, Dept Med Lab Technol, Jeddah, Saudi Arabia
Bandres-Ciga, S:
NIA, Lab Neurogenet, Bethesda, MD USA
Finan, C:
UCL, Fac Populat Hlth, Inst Cardiovasc Sci, London WC1E 6BT, England
Univ Coll London, British Heart Fdn Res Accelerator Ctr, New Delhi, India
Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands
Hingorani, AD:
UCL, Fac Populat Hlth, Inst Cardiovasc Sci, London WC1E 6BT, England
Univ Coll London, British Heart Fdn Res Accelerator Ctr, New Delhi, India
Hlth Data Res UK, 222 Euston Rd, London, England
Wood, NW:
UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England
Clarimón, J.:
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Dols-Icardo O.:
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Kulisevsky J.:
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Marín J.:
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Pagonabarraga J.:
Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Department of Neurology, Hospital Universitario Infanta Sofía, Madrid, Spain
Lynch, Timothy L.:
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland
Green Published, gold
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