Cargando…
Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates
Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving in silico screening of compounds from a large-s...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928862/ https://www.ncbi.nlm.nih.gov/pubmed/33577681 http://dx.doi.org/10.1093/hmg/ddab049 |
_version_ | 1783659899811528704 |
---|---|
author | Konuma, Takahiro Ogawa, Kotaro Okada, Yukinori |
author_facet | Konuma, Takahiro Ogawa, Kotaro Okada, Yukinori |
author_sort | Konuma, Takahiro |
collection | PubMed |
description | Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving in silico screening of compounds from a large-scale pharmacological database (L1000 Connectivity Map), which have inverse expression profiles compared with tissue-specific genetically regulated gene expression. Firstly we confirmed the statistical robustness by the application of the null GWAS data and enrichment in the true-positive drug–disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, then we applied the GWAS summary statistics of large-scale European meta-analysis (17 traits; n(average) = 201 849) and the hospitalized COVID-19 (n = 900 687), which has urgent need for drug development. We detected potential therapeutic compounds as well as anisomycin in schizophrenia (false discovery rate (FDR)-q = 0.056) and verapamil in hospitalized COVID-19 (FDR-q = 0.068) as top-associated compounds. This approach could be effective in disease genomics-driven drug development. |
format | Online Article Text |
id | pubmed-7928862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-79288622021-03-04 Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates Konuma, Takahiro Ogawa, Kotaro Okada, Yukinori Hum Mol Genet Bioinformatics Article Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving in silico screening of compounds from a large-scale pharmacological database (L1000 Connectivity Map), which have inverse expression profiles compared with tissue-specific genetically regulated gene expression. Firstly we confirmed the statistical robustness by the application of the null GWAS data and enrichment in the true-positive drug–disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, then we applied the GWAS summary statistics of large-scale European meta-analysis (17 traits; n(average) = 201 849) and the hospitalized COVID-19 (n = 900 687), which has urgent need for drug development. We detected potential therapeutic compounds as well as anisomycin in schizophrenia (false discovery rate (FDR)-q = 0.056) and verapamil in hospitalized COVID-19 (FDR-q = 0.068) as top-associated compounds. This approach could be effective in disease genomics-driven drug development. Oxford University Press 2021-02-13 /pmc/articles/PMC7928862/ /pubmed/33577681 http://dx.doi.org/10.1093/hmg/ddab049 Text en © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Bioinformatics Article Konuma, Takahiro Ogawa, Kotaro Okada, Yukinori Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
title | Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
title_full | Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
title_fullStr | Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
title_full_unstemmed | Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
title_short | Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
title_sort | integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates |
topic | Bioinformatics Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928862/ https://www.ncbi.nlm.nih.gov/pubmed/33577681 http://dx.doi.org/10.1093/hmg/ddab049 |
work_keys_str_mv | AT konumatakahiro integrationofgeneticallyregulatedgeneexpressionandpharmacologicallibraryprovidestherapeuticdrugcandidates AT ogawakotaro integrationofgeneticallyregulatedgeneexpressionandpharmacologicallibraryprovidestherapeuticdrugcandidates AT okadayukinori integrationofgeneticallyregulatedgeneexpressionandpharmacologicallibraryprovidestherapeuticdrugcandidates |