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

Wen Zhang, Georgios Voloudakis, Veera M. Rajagopal, Ben Readhead, Joel T. Dudley, Eric E. Schadt, Johan L. M. Björkegren, Yungil Kim, John F. Fullard, Gabriel E. Hoffman and Panos Roussos ()
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Wen Zhang: Icahn School of Medicine at Mount Sinai
Georgios Voloudakis: Icahn School of Medicine at Mount Sinai
Veera M. Rajagopal: Icahn School of Medicine at Mount Sinai
Ben Readhead: Icahn School of Medicine at Mount Sinai
Joel T. Dudley: Icahn School of Medicine at Mount Sinai
Eric E. Schadt: Icahn School of Medicine at Mount Sinai
Johan L. M. Björkegren: Icahn School of Medicine at Mount Sinai
Yungil Kim: Icahn School of Medicine at Mount Sinai
John F. Fullard: Icahn School of Medicine at Mount Sinai
Gabriel E. Hoffman: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11874-7

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