Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders

Psychiatric disorders impose tremendous economic burden on society and are leading causes of disability worldwide. However, only limited drugs are available for psychiatric disorders and the efficacy of most currently used drugs is poor for many patients. To identify novel therapeutic targets for ps...

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Bibliographic Details
Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2023-01, Vol.48 (2), p.270-280
Main Authors: Liu, Jiewei, Cheng, Yuqi, Li, Ming, Zhang, Zhijun, Li, Tao, Luo, Xiong-Jian
Format: Article
Language:English
Subjects:
Attention deficit hyperactivity disorder
Bipolar disorder
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Drb1 protein
Drug development
Drugs
Gene expression
Genetic Predisposition to Disease
Genome-wide association studies
Genome-Wide Association Study
Genomes
HLA-DRB1 Chains - genetics
Humans
Mendelian Randomization Analysis
Mental depression
Mental disorders
Mental Disorders - genetics
Polymorphism, Single Nucleotide - genetics
Proteasome Endopeptidase Complex - genetics
Proteome - genetics
Proteomes
Proteomics
Quantitative trait loci
Schizophrenia
Therapeutic applications
Therapeutic targets
Transcriptomes
Transcriptomics
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Summary:Psychiatric disorders impose tremendous economic burden on society and are leading causes of disability worldwide. However, only limited drugs are available for psychiatric disorders and the efficacy of most currently used drugs is poor for many patients. To identify novel therapeutic targets for psychiatric disorders, we performed genome-wide Mendelian randomization analyses by integrating brain-derived molecular quantitative trait loci (mRNA expression and protein abundance quantitative trait loci) of 1263 actionable proteins (targeted by approved drugs or drugs in clinical phase of development) and genetic findings from large-scale genome-wide association studies (GWASs). Using transcriptome data, we identified 25 potential drug targets for psychiatric disorders, including 12 genes for schizophrenia, 7 for bipolar disorder, 7 for depression, and 1 (TIE1) for attention deficit and hyperactivity. We also identified 10 actionable drug targets by using brain proteome data, including 4 (HLA-DRB1, CAMKK2, P2RX7, and MAPK3) for schizophrenia, 1 (PRKCB) for bipolar disorder, 6 (PSMB4, IMPDH2, SERPINC1, GRIA1, P2RX7 and TAOK3) for depression. Of note, MAPK3 and HLA-DRB1 were supported by both transcriptome and proteome-wide MR analyses, suggesting that these two proteins are promising therapeutic targets for schizophrenia. Our study shows the power of integrating large-scale GWAS findings and transcriptomic and proteomic data in identifying actionable drug targets. Besides, our findings prioritize actionable novel drug targets for development of new therapeutics and provide critical drug-repurposing opportunities for psychiatric disorders.
ISSN:0893-133X
1740-634X
DOI:10.1038/s41386-022-01456-5