Integrative transcriptome imputation reveals tissue-specific and shared biological mechanisms mediating susceptibility to complex traits

Wen Zhang, Georgios Voloudakis, Veera M. Rajagopal, Benjamin Readhead, Joel T. Dudley, Eric E. Schadt, Johan L.M. Björkegren, Yungil Kim, John F. Fullard, Gabriel E. Hoffman, Panos Roussos

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Transcriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional importance of genetic variation on gene expression, we generate a small but significant improvement in the accuracy of transcriptome prediction and increase the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge on biological processes and relevant phenotypes in human and mouse phenotype databases. We perform drug repurposing analysis and identify compounds that mimic, or reverse, trait-specific changes. We identify genes that exhibit agonistic pleiotropy for genetically correlated traits that converge on shared biological pathways and elucidate distinct processes in disease etiopathogenesis. Overall, this comprehensive analysis provides insight into the specificity and convergence of gene expression on susceptibility to complex traits.

Original languageEnglish (US)
Article number3834
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Zhang, W., Voloudakis, G., Rajagopal, V. M., Readhead, B., Dudley, J. T., Schadt, E. E., Björkegren, J. L. M., Kim, Y., Fullard, J. F., Hoffman, G. E., & Roussos, P. (2019). Integrative transcriptome imputation reveals tissue-specific and shared biological mechanisms mediating susceptibility to complex traits. Nature communications, 10(1), [3834]. https://doi.org/10.1038/s41467-019-11874-7