Molecular characterization of the stress network in individuals at risk for schizophrenia

Abstract

The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low (healthy siblings of schizophrenia patients) or high (healthy controls) stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. ADCYAP1, GABRB1, SSTR1, and TNFRSF12A), neurotransmitter receptors (e.g. GRIN3A, SSTR1, GABRB1, and HTR1E), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, IGSF11, and PKIA). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for schizophrenia and other psychiatric disorders and play a role in mounting an adaptive stress response in at-risk individuals, making them potentially druggable targets for stress-related diseases.

Keywords: Molecular correlates; Stress network; Stress reactivity; Stress sensitivity; Stress-related diseases.

Fig. 1

Study overview. (A) Cortical brain regions vulnerable to stress (= stress network) during an emotion processing task in siblings of schizophrenia patients compared to healthy controls were assessed in an fMRI study. All brain regions showed higher stress-induced brain activity following an acute social stressor in at-risk individuals (healthy siblings of schizophrenia patients). The fMRI data was mapped to the AHBA resulting in an overlay of the fMRI and gene expression data. (B) With this overlay, differential gene expression between the brain regions vulnerable to stress and the rest of the cortex were assessed. (C) Differentially expressed genes were consequently characterized by identifying enrichment for gene ontology and cell type markers, associations with stress-related diseases and enrichment for cortisol responsive genes. (D) Information provided by the previous analyses was used to build a model of a molecular pathway underlying human stress reactivity.

Fig. 2

Differentially expressed genes in brain regions vulnerable to stress based on siblings of schizophrenia patients can be identified using gene expression atlases. (A) Brain regions in our stress network are present throughout the brain (including cerebellum, cingulate gyrus, frontal gyrus, temporal gyrus, and hippocampal formation). For the analysis, all regions in the cortex were combined. (B) Differential gene expression was determined for our cortical stress network compared to the rest of the cortex. Significant genes (BH-adjusted p-value < 0.05) have higher expression in our stress network. Grey dots represent non-significant genes and brown dots represent significant genes based on meta-analysis across all six AHBA donors. (C) The box plots show the expression of the higher (left) and lower (right) expressed genes compared to the rest of the cortex in the brain regions of interest from our stress network. (D) In the whole brain, differentially expressed genes show mostly high expression levels in the cortex and low expression levels in non-cortical brain regions. In the heatmap, each row represents a gene and each column represents a sample and all samples of the AHBA are illustrated here. On the right, coronal brain sections for the genes SSTR1, GABRB1, ADCYAP1, and DOC2A are presented. Colors indicates high (red) and low (blue) expression levels. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Functionality of differentially expressed genes in our stress network based on siblings of schizophrenia patients. (A) Differentially expressed genes annotated to one of the GO terms were assigned to multiple GO terms and thus involved in multiple processes. Between parenthesis, the total number of genes assigned to the GO term is depicted. On the right side of the graph, ORs are displayed per GO term. (B) Differentially expressed genes (brown), neuronal marker genes (purple) and overlapping genes (yellow) are plotted in a t-SNE plot generated using BrainScope.nl (Huisman et al., 2017), where points close together represent genes with similar gene expression profiles. The differentially expressed genes show a similar profile in the t-SNE plot as neuronal cell markers (purple). (C) The sum of the log₁₀ values of the counts per gene is plotted for each cell cluster. Green clusters belong to GABAergic cells, purple clusters to glutamatergic cells and red clusters to non-neuronal cells. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Differentially expressed genes in the stress network based on siblings of schizophrenia patients and in other stress-related psychiatric disorders Disease risk gene enrichment was performed for the differentially expressed genes. The diseases are clustered as non-brain related disease, brain disease and psychiatric disease. As a non-disease-associated set of genes, waste-hip ratio and height were used. Numbers between the parenthesis indicate the number of genes known to be associated with the disease, based on DisGeNet. The effect size of the gene enrichment is presented at the middle part of the figure and considered significant when the BH-adjusted p-value < 0.05 (*). Blue bars mean depletion of genes, whereas red bars indicate enrichment of genes in a trait. ORs for the amount of receptors in the set of differentially expressed genes are depicted for every trait (shown on the right side of the graph). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)