Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders

Abstract

Neuroinflammation has been implicated in multiple brain disorders but the extent and the magnitude of change in immune-related genes (IRGs) across distinct brain disorders has not been directly compared. In this study, 1275 IRGs were curated and their expression changes investigated in 2467 postmortem brains of controls and patients with six major brain disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD). There were 865 IRGs present across all microarray and RNA-seq datasets. More than 60% of the IRGs had significantly altered expression in at least one of the six disorders. The differentially expressed immune-related genes (dIRGs) shared across disorders were mainly related to innate immunity. Moreover, sex, tissue, and putative cell type were systematically evaluated for immune alterations in different neuropsychiatric disorders. Co-expression networks revealed that transcripts of the neuroimmune systems interacted with neuronal-systems, both of which contribute to the pathology of brain disorders. However, only a few genes with expression changes were also identified as containing risk variants in genome-wide association studies. The transcriptome alterations at gene and network levels may clarify the immune-related pathophysiology and help to better define neuropsychiatric and neurological disorders.

Fig. 1.. Differential expression of immune genes in six disorders.

A. Volcano plot for each disorder. B. Effect size correlation between microarray data and RNA-seq data.

Fig. 2.. Comparison of the effect size of differentially expressed IRGs among neuropsychiatric disease pairs.

A. Numbers of up-regulated and downregulated dIRGs in the six disorders. Red represents up-regulated dIRGs, blue represents down-regulated dIRGs. B. Cluster tree of scaled effect size for all disorders based on 1,275 IRGs for their fold changes. C. Significant sex differences by effect size in ASD and MDD. The dash line indicated mean value of effect size. D. dIRGs shared across disorders: CRH and TAC1. *: fdr qvalue<0.05; **fdr qvalue<0.01; ***fdr qvalue<0.001

Fig. 3.. Comparing dIRG-associated function across disorders.

A. UpSet plot of dIRGs overlap between pairs of disorders. Dark cells and lines indicate that the set participates in the intersection. B. The doughnut chart shows the percentages of different IRGs types. C. UpSet plot of differential immune pathways overlap. The black dots and the black line show the overlapping dIRG-pathways between pairs of disorders. Cells that are dark indicate that it participates in the intersection. D. The doughnut chart shows the percentages of overlapping dIRG-pathways. E. Gene ontology enrichment analysis results of six pathways shared by dIRGs of all six disorders.

Fig. 4.. Shared immune-related coexpression modules

A. Robust gene dendrogram obtained by WGCNA. B. The multidimensional scaling plot demonstrates the relationship between modules. Modules highlighted by stars are enriched in immune genes (enrichment qvalue < 0.05). Edges are weighted by the strength of correlation between eigengenes of modules. C. The top 20 hub genes are plotted for the three IRM4, IRM12, and IRM14. A complete list of genes’ module membership (kME) is provided in data Table S8. Edges are weighted by the strength of the correlation between genes. D. Relationships of module eigengenes and diseases. Numbers in the table report the correlations of the corresponding module eigengenes and traits, with the p.values printed below the correlation coefficients r values. E. Cell marker enrichment of shared IRMs. F. Enrichment of the shared IRMs in pathways. Yellow: IRM4, Tan: IRM12, Cyan: IRM14

Fig. 5.. Disease-specific coexpression modules.

A. Workflow for identifying disease-specific IRMs. B. Module preservation plot of disease-specific IRMs. The median rank and Zsummary statistics of module preservation of disorder modules in background modules (y-axis) vs. module size (x-axis). C. Pathway enrichment of disease-specific immune modules.