Major Depressive Disorder Is Associated With Differential Expression of Innate Immune and Neutrophil-Related Gene Networks in Peripheral Blood: A Quantitative Review of Whole-Genome Transcriptional Data From Case-Control Studies.

Abstract

Background: Whole genome transcription has been measured in peripheral blood samples as a candidate biomarker of inflammation associated with major depressive disorder (MDD).

Methods: We searched for all MDD case-control studies that reported microarray or RNAseq measurements on whole blood or peripheral blood mononuclear cells (PBMCs). Primary datasets were re-analysed, when openly accessible, to estimate case-control differences, and to evaluate the functional roles of differentially expressed gene lists, by technically harmonized methods.

Results: We found 10 eligible studies, comprising N=1,754 depressed cases and N=1,145 healthy controls. 52 genes were called significant by two of the primary studies (published overlap list). After harmonization of analysis across 8 accessible datasets (N=1,706 cases, 1,098 controls), 272 genes were coincidentally listed in the top 3% most differentially expressed genes in two or more studies of whole blood or PBMCs with concordant direction-of-effect (harmonized overlap list). By meta-analysis of standardized mean difference (SMD) across 4 studies of whole blood samples (N=1,567 cases, 954 controls), 343 genes were found with false discovery rate < 5% (SMD meta-analysis list). These 3 lists intersected significantly. Genes abnormally expressed in MDD were enriched for innate immune related functions, coded for non-random protein-protein interaction networks, and co-expressed in the normative transcriptome module specialized for innate immune and neutrophil functions.

Conclusions: Quantitative review of existing case-control data provided robust evidence for abnormal expression of gene networks important for the regulation and implementation of innate immune response. Further development of white blood cell transcriptional biomarkers for inflamed depression seems warranted.