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

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 (NGS) 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 dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden-death medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA expression (9 samples per group). DeSeq2 identified thirty-five 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.

Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data

“…Recently (Pantazatos et al, 2017) used an early release of the databases to interpret expression patterns in the cortex of suicide victims, suggesting involvement of microglia. Moreover, this database has further applications beyond the use of marker genes, such as understanding the molecular basis of cellular electrophysiological diversity (Tripathy et al, 2017).…”

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder

“…Pantazatos et al [54] reported an increased expression of genes involved in “DNA-dependent ATPase activity” in suicides compared to nonsuicides ( p < 0.1 corrected). Therefore, we anticipate that future studies focusing on the mitochondrial function of subjects with suicidal behavior may help to clarify the role of this process in suicide.…”

Cross-laboratory analysis of brain cell type transcriptomes with applications to interpretation of bulk tissue data

“…Recently (Pantazatos et al, 2016) used an early release of the databases to interpret expression patterns in the cortex of suicide victims, suggesting involvement of microglia. Moreover, this database has further applications beyond the use of marker genes, such as understanding the molecular basis of cellular diversity (Tripathy et al, 2017).…”