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

Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific...

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Published in:	Biological psychiatry (1969) Vol. 83; no. 1; pp. 70 - 80
Main Authors:	Leday, Gwenaël G.R., Vértes, Petra E., Richardson, Sylvia, Greene, Jonathan R., Regan, Tim, Khan, Shahid, Henderson, Robbie, Freeman, Tom C., Pariante, Carmine M., Harrison, Neil A., Bullmore, Edward, Vertes, Petra, Cardinal, Rudolf, Leday, Gwenael, Freeman, Tom, Hume, David, Wu, Zhaozong, Pariante, Carmine, Cattaneo, Annamaria, Zunszain, Patricia, Borsini, Alessandra, Stewart, Robert, Chandran, David, Carvalho, Livia, Bell, Joshua, Souza-Teodoro, Luis, Perry, Hugh, Harrison, Neil, Drevets, Wayne, Wittenberg, Gayle, Jones, Declan, Stylianou, Annie, Perry, V. Hugh, Drevets, Wayne C., Wittenberg, Gayle M., Bullmore, Edward T.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01.01.2018 Elsevier
Subjects:	Affymetrix Bayesian Biomarker Biomarkers - blood Case-Control Studies Depressive Disorder, Major - blood Depressive Disorder, Major - genetics Depressive Disorder, Major - immunology Gene Expression Gene Expression Regulation Humans Immunity, Innate - genetics Inflammation Microarray Analysis Psychiatric/Mental Health Systems Transcriptome Wernicke Encephalopathy Biomarker Inflammation Affymetrix Systems Bayesian Transcriptome
ISSN:	0006-3223, 1873-2402, 1873-2402
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Abstract	Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. We 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. A 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). 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.
AbstractList	Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.BACKGROUNDPeripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.We 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.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.A 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).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).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.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. Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. We 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. A 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). 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. AbstractBackgroundPeripheral 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.
Author	Greene, Jonathan R. Freeman, Tom Cardinal, Rudolf Wu, Zhaozong Henderson, Robbie Drevets, Wayne Borsini, Alessandra Chandran, David Wittenberg, Gayle M. Hume, David Wittenberg, Gayle Drevets, Wayne C. Regan, Tim Perry, V. Hugh Souza-Teodoro, Luis Bullmore, Edward T. Leday, Gwenaël G.R. Richardson, Sylvia Bullmore, Edward Leday, Gwenael Cattaneo, Annamaria Vértes, Petra E. Stewart, Robert Khan, Shahid Jones, Declan Bell, Joshua Pariante, Carmine M. Pariante, Carmine Stylianou, Annie Harrison, Neil Harrison, Neil A. Zunszain, Patricia Carvalho, Livia Perry, Hugh Freeman, Tom C. Vertes, Petra
AuthorAffiliation	a Medical Research Council Biostatistics Unit, Cambridge, United Kingdom e ImmunoPsychiatry, GlaxoSmithKline Research & Development, Stevenage, United Kingdom f Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom i Rancho BioSciences, San Diego, California b Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom h Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom d Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom g Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom j Janssen Research & Development, Titusville, New Jersey c Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/28688579$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Contributor	Freeman, Tom Cardinal, Rudolf Wu, Zhaozong Drevets, Wayne Henderson, Robbie Borsini, Alessandra Chandran, David Hume, David Wittenberg, Gayle Regan, Tim Souza-Teodoro, Luis Richardson, Sylvia Bullmore, Edward Leday, Gwenael Cattaneo, Annamaria Stewart, Robert Khan, Shahid Jones, Declan Bell, Joshua Pariante, Carmine Stylianou, Annie Harrison, Neil Zunszain, Patricia Carvalho, Livia Perry, Hugh Vertes, Petra
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Copyright	2017 Society of Biological Psychiatry Society of Biological Psychiatry Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. 2017 Society of Biological Psychiatry. All rights reserved. 2017 Society of Biological Psychiatry
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Snippet	Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.... AbstractBackgroundPeripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus... Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of...
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SubjectTerms	Affymetrix Bayesian Biomarker Biomarkers - blood Case-Control Studies Depressive Disorder, Major - blood Depressive Disorder, Major - genetics Depressive Disorder, Major - immunology Gene Expression Gene Expression Regulation Humans Immunity, Innate - genetics Inflammation Microarray Analysis Psychiatric/Mental Health Systems Transcriptome Wernicke Encephalopathy
Title	Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder
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