Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder

Gwenaël G R Leday ,Greene ,Perry Vh ,Carmine M Pariante ,Shahid A Khan ,Robert B Henderson ,Tim Regan ,Drevets Wc ,Tom C Freeman ,Wittenberg Gm ,Sylvia Richardson ,Petra E Vértes ,Neil A Harrison ,Bullmore Et

doi:10.1016/j.biopsych.2017.01.021

Abstract

BackgroundPeripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. MethodsWe used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. ResultsA total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies). ConclusionsMDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.

Highlights

Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation
The Bayesian method identified q2 = .0246 as the largest p value threshold associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance
We have reported the differential expression analysis of wholegenome microarray data from two independent case-control studies of patients with MDD compared with healthy control subjects

Summary

Introduction

Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. The MDD patients with overexpression of UP genes had underexpression of DOWN genes CONCLUSIONS: MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression

Methods

Results

Conclusion