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

Hum Mol Genet. 2021 Apr 26;30(3-4):294-304. doi: 10.1093/hmg/ddab049.

Abstract

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; 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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anisomycin / pharmacology
  • COVID-19 Drug Treatment*
  • Databases, Genetic
  • Databases, Pharmaceutical
  • Drug Development / methods*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Genome-Wide Association Study / methods*
  • Genome-Wide Association Study / statistics & numerical data*
  • Genomics / methods
  • Humans
  • Pharmaceutical Preparations
  • Schizophrenia / drug therapy*
  • Software
  • Transcriptome / genetics*
  • Verapamil / pharmacology

Substances

  • Pharmaceutical Preparations
  • Anisomycin
  • Verapamil