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

Konuma, Takahiro; Ogawa, Kotaro; Okada, Yukinori

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 robustness 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; 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 (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.