Gene Sets Altered Across Brain Regions in Schizophrenia, Bipolar Disorder & MDD

Until now, the majority of postmortem research that has examined functionally related gene sets has been limited to a single disorder or region of the brain.
Until now, the majority of postmortem research that has examined functionally related gene sets has been limited to a single disorder or region of the brain.

A large RNA sequencing study by scientists at Johns Hopkins University School of Medicine has identified gene sets that are consistently dysregulated across brain regions in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). The findings were published in September 2016 in Translational Psychiatry.1

Of the polymorphisms that have been linked with the risk of SCZ, BD, or MDD in genome-wide association studies (GWAS), the most informative ones similarly predict all 3 disorders. Previous functional analysis determined that “pathways that regulate histone methylation and thereby gene transcription are the most strongly implicated on the basis of the shared genetics across the three disorders, followed by immune and signaling pathways,” though their impact on gene expression in the brain has not been elucidated, wrote the authors of the current study.2,3

The majority of postmortem research that has examined functionally related gene sets has been limited to a single disorder or region of the brain, and core processes that are shared across diagnoses and brain regions are unclear. Deficits related to psychiatric disorders have been identified in almost every brain region, ranging from gray and white matter deficits in the superior temporal gyrus, left medial temporal lobe, frontal temporal lobe, and occipital lobe in schizophrenia; to reduced gray matter in the frontal temporal lobe in BD; and decreased gray matter volume in the orbitofrontal cortex in MDD. Various deficits in structure, connectivity, and gene expression have also been found across disorders, suggesting that molecular deficits in such disorders likely impact the entire brain.

Findings from prior epigenetic and expression studies revealed “co-expression modules that are preserved across tissues, supporting the notion that polymorphisms will result in similar deficits in different cell types,” according to the present authors, and “expression levels of key genes in the preserved modules tended to be more heritable than genes in modules that were not preserved.” They proposed that mechanisms underlying gene expression may have similar effects on multiple regions of the brain, and that those that show consistency across regions are more likely than others to represent key pathways in the etiology of SCZ, BD, and MDD.

To that end, the researchers performed RNA sequencing to measure gene expression in 157 postmortem brains from the Stanley Array Collection and the Stanley Neuropathology Consortium. They first examined the hippocampus of 100 brains, and then replicated the experiment in the orbitofrontal cortex of 57 brains. Additionally, they used gene set enrichment analysis (GSEA) to identify gene sets with a disproportionate number of overexpressed or under-expressed genes.

The results revealed 13 sets of genes that replicated in SCZ and BPD across brain regions and were also found to be enriched in MDD. In the hippocampus, the gene sets showed significantly altered expression for SCZ and BD, and there was altered expression in the orbitofrontal cortex for all 3 disorders. Ribosomal genes were overexpressed, while those involved in neuronal systems, GABAergic signaling, endocytosis and antigen degradation were under-expressed in all 3 disorders, compared to healthy controls.

“Our findings establish the central importance of these pathways by demonstrating that they are consistently altered in all diagnosis groups in two brain regions from two cohorts,” the authors concluded. These data suggest that RNA processing and protein synthesis may be worthy targets of future research investigating novel treatments for SCZ, BD, and MDD.

References

1. Darby MM, Yolken RH, Sabunciyan S. Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders. Transl Psychiatry. 2016; 6(9):e890.

2. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013; 381: 1371–1379.

3. Schulze TG, Akula N, Breuer R, et al. Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder. World J Biol Psychiatry. 2014; 15: 200-208.

4. Cai C, Langfelder P, Fuller TF, et al. Is human blood a good surrogate for brain tissue in transcriptional studies? BMC Genomics. 2010; 11: 589.

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