Effect of Chronic Stress on Whole Blood Transcriptome: A Meta-Analysis of Publicly Available Datasets from Rodent Models

Abstract

BackgroundChronic stress increases risk for neuropsychiatric disorders in humans. By modeling stress-induced changes in animals, we may improve diagnosis or treatment of these disorders. Successful translation benefits from studies with sufficient statistical power and outcome measurements that can be directly compared across species. We performed a meta-analysis to examine the impact of chronic stress on the whole blood transcriptome. MethodsDatasets were systematically identified in Gemma, a database of reprocessed public transcriptional profiling studies; datasets GSE68076, GSE72262, and GSE84185 met inclusion/exclusion parameters. Each study exposed eight-week old mice to chronic stress (5-10 days social defeat stress or 6-8 weeks chronic mild stress). The final sample size was n=92 (n=45 Non-Stress/n=47 Stress). Stress-related differential expression in each dataset was quantified using the Limma pipeline followed by empirical Bayes moderation. For the 9,219 genes represented in all three datasets, we ran a meta-analysis of Log(2) Fold Changes using a random effects model and corrected for false discovery rate (FDR). Functional patterns were assessed with fast Gene Set Enrichment Analysis. Cell type specific enrichment for each of the differentially expressed genes was further explored using a public 10x genomics scRNA-Seq dataset from mouse peripheral blood mononuclear cells. ResultsFindings included 23 downregulated and 16 upregulated transcripts in stress-exposed mice (FDR View larger version (20K): org.highwire.dtl.DTLVardef@161fc2eorg.highwire.dtl.DTLVardef@1f358b9org.highwire.dtl.DTLVardef@145ef33org.highwire.dtl.DTLVardef@5b1169_HPS_FORMAT_FIGEXP M_FIG C_FIG Key pointsSuccessful translational research benefits from studies with outcome measurements that can be directly compared across species and sufficient statistical power. The present report is a meta-analysis of three mouse experiments examining the impact of chronic stress on the whole blood transcriptome. Our results provide insight into stress-related immune dysregulation and add weight to the hypothesis that environmental stress escalates cellular aging. These findings illustrate the utility of the blood transcriptome as a bridge between human and rodent models.