Edward T. Bullmore

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

Background Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Methods 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. Results 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). 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.

Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia.

Background Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. Methods We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. Results Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. Conclusions Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients.

Data supporting NSPN publication "Structural covariance networks are coupled to expression of genes enriched in supragranular layers of the human cortex "

Gene expression matrices for the Desikan-Killiany atlas (68 regions) and the high-resolution parcellation that includes 308 regions of 500m2 each.

Emerging personality dimensions during adolescence and young adulthood are underpinned by a latent trait indexing impairment in social functioning

This research was supported by the Wellcome Trust Strategic Award (095844/Z/11/Z) held by authors: IMG, ETB, PBJ, RD, PF.

Effects of anti‐inflammatory drugs on the expression of tryptophan‐metabolism genes by human macrophages

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti‐TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti‐inflammatory drugs (indomethacin, prednisolone, and anti‐TNFα antibody) on the response of human monocyte‐derived macrophages (MDMs) from 6 individuals to LPS or IFN‐α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti‐inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression—notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti‐TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.

Data supporting NSPN publication "Adolescent tuning of association cortex in human structural brain networks"

There are two files supporting this publication. The first is an RData file containing all variables necessary to reproduce the main findings of the publication. The second is a Microsoft Word document describing 1) how the data was collected and processed and 2) all the variables stored in the RData file.

Data supporting publication "Probabilistic thresholding of functional connectomes: application to schizophrenia"

There are two files supporting this publication. The first is a .zip file containing six .mat files, which include all variables necessary to reproduce the main findings of the publication. The second is a Microsoft Word document describing 1) how the data was collected and processed and 2) all the variables stored in the .mat files.

Data supporting NSPN publication "Characterising the latent structure and organisation of self-reported thoughts, feelings and behaviours in adolescents and young adults"

There are two data files supporting this publication. The first is the main file, which included all raw data used to create the bifactor structure reported in the paper. We have also included the saved factors scores as well as the latent profile subgroup classification. All variables used in the discriminant validity are included. Additionally there are sum scores relating to the individual measurements used in the factor analysis for both the entire cohort analysed in the main paper as well as 29 additional participants who were excluded due to missing data problems. The second data file contains both individuals included in NSPN as well as those who were considered “non-responders”. This includes basic demographic information which was used to compare responders with non-responders in the resulting paper.