Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome
Autoři:
Denis A. Baird aff001; Jimmy Z. Liu aff002; Jie Zheng aff001; Solveig K. Sieberts aff003; Thanneer Perumal aff003; Benjamin Elsworth aff001; Tom G. Richardson aff001; Chia-Yen Chen aff002; Minerva M. Carrasquillo aff004; Mariet Allen aff004; Joseph S. Reddy aff005; Philip L. De Jager aff006; Nilufer Ertekin-Taner aff004; Lara M. Mangravite aff003; Ben Logsdon aff003; Karol Estrada aff002; Philip C. Haycock aff001; Gibran Hemani aff001; Heiko Runz aff002; George Davey Smith aff001; Tom R. Gaunt aff001;
Působiště autorů:
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom
aff001; Translational Biology, Research and Development, Cambridge, Massachusetts, United States of America
aff002; Sage Bionetworks, Seattle, Washington, United States of America
aff003; Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, United States of America
aff004; Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, Florida, United States of America
aff005; Centre for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Centre, New York, New York, United States of America
aff006; Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Centre, New York, New York, United States of America
aff007; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, United States of America
aff008; BioMarin Pharmaceuticals, San Rafael, California, United States of America
aff009; NIHR Bristol Biomedical Research Centre, Oakfield House, University of Bristol, Bristol, United Kingdom
aff010
Vyšlo v časopise:
Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome. PLoS Genet 17(1): e1009224. doi:10.1371/journal.pgen.1009224
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009224
Souhrn
Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer’s Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer’s disease, 6 genes with Parkinson’s disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
Klíčová slova:
Alzheimer's disease – Amyotrophic lateral sclerosis – Drug discovery – Gene expression – Genetics of disease – Medical risk factors – Parkinson disease – Schizophrenia
Zdroje
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