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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483418/ https://www.ncbi.nlm.nih.gov/pubmed/36114287 http://dx.doi.org/10.1038/s41386-022-01456-5 |
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author | Liu, Jiewei Cheng, Yuqi Li, Ming Zhang, Zhijun Li, Tao Luo, Xiong-Jian |
author_facet | Liu, Jiewei Cheng, Yuqi Li, Ming Zhang, Zhijun Li, Tao Luo, Xiong-Jian |
author_sort | Liu, Jiewei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9483418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-94834182022-09-19 Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders Liu, Jiewei Cheng, Yuqi Li, Ming Zhang, Zhijun Li, Tao Luo, Xiong-Jian Neuropsychopharmacology Article 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. Springer International Publishing 2022-09-16 2023-01 /pmc/articles/PMC9483418/ /pubmed/36114287 http://dx.doi.org/10.1038/s41386-022-01456-5 Text en © The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
spellingShingle | Article Liu, Jiewei Cheng, Yuqi Li, Ming Zhang, Zhijun Li, Tao Luo, Xiong-Jian Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
title | Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
title_full | Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
title_fullStr | Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
title_full_unstemmed | Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
title_short | Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
title_sort | genome-wide mendelian randomization identifies actionable novel drug targets for psychiatric disorders |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483418/ https://www.ncbi.nlm.nih.gov/pubmed/36114287 http://dx.doi.org/10.1038/s41386-022-01456-5 |
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