Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity

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Abstract

Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted P<0.1). In depression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO analysis suggests lower expression of genes involved in oligodendrocyte differentiation, regulation of glutamatergic neurotransmission, and oxytocin receptor expression in both suicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) in depression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood–brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorders.

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Acknowledgements

This research was funded by NIMH 5R01MH082041-05 (PI: JJM), a Paul Janssen Translational Neuroscience Postdoctoral Fellowship (to SPP) and an NIMH K01MH108721 (PI: SPP). Collection and psychiatric characterization of brain samples was supported by MH40210 (PI: VA), MH062185 (PI: JJM) and MH064168 (PI: AJD). We thank Hanga Galfalvy for helpful comments and suggestions regarding data analysis, Peter L Nagy, Jane Dunning-Broadbent, Stuart J Andrews and Jiuhong Pang for contributions to RNA sequencing, data processing, interpretation and analysis, and John Repass at ARG Genetics for conducting qPCR validation experiments.

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Correspondence to S P Pantazatos or J J Mann.

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The authors have no relevant conflicts of interest to report. JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene.

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