Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates

Takahiro Konuma, Kotaro Ogawa, Yukinori Okada
2021 Human Molecular Genetics  
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) that have inverse expression profiles compared to tissue-specific genetically regulated gene expression. After confirmation of the statistical
more » ... tness by the application of the null GWAS data and of enrichment in true-positive drug-disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, we applied GWAS summary statistics of large-scale European meta-analysis (17 traits; naverage = 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 (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.
doi:10.1093/hmg/ddab049 pmid:33577681 pmcid:PMC7928862 fatcat:yjhi3uga3jc27i6uctish7wltm