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Published on: February 24, 2023
Molecular pathway reconstruction and analysis of disturbed gene expression in depressed individuals who died by
Vladimir Zhurov1, John D H Stead, Zul Merali
1Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
Abstract:
Molecular mechanisms behind the etiology and pathophysiology of major depressive disorder and suicide remain largely unknown. Recent molecular studies of expression of serotonin, GABA and CRH receptors in various brain regions have demonstrated that molecular factors may contribute to the development of depressive disorder and suicide behaviour. Here, we used microarray analysis to examine the expression of genes in brain tissue (frontopolar cortex) of individuals who had been diagnosed with major depressive disorder and died by suicide, and those who had died suddenly without a history of depression. We analyzed the list of differentially expressed genes using pathway analysis, which is an assumption-free approach to analyze microarray data. Our analysis revealed that the differentially expressed genes formed functional networks that were implicated in cell to cell signaling related to synapse maturation, neuronal growth and neuronal complexity. We further validated these data by randomly choosing (100 times) similarly sized gene lists and subjecting these lists to the same analyses. Random gene lists did not provide highly connected gene networks like those generated by the differentially expressed list derived from our samples. We also found through correlational analysis that the gene expression of control participants was more highly coordinated than in the MDD/suicide group. These data suggest that among depressed individuals who died by suicide, wide ranging perturbations of gene expression exist that are critical for normal synaptic connectively, morphology and cell to cell communication.
Insights
Major depressive disorder and suicide are linked to significant gene expression changes in the brain, affecting neuronal growth and communication. These findings highlight molecular disruptions critical for synaptic function in individuals with major depressive disorder (MDD) who died by suicide.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- The molecular underpinnings of major depressive disorder (MDD) and suicide are not well understood.
- Previous studies suggest alterations in neurotransmitter receptor expression may play a role.
- Identifying specific gene expression patterns could elucidate the pathophysiology of MDD and suicide.
Purpose of the Study:
- To investigate gene expression differences in the frontopolar cortex of individuals with MDD who died by suicide compared to controls.
- To identify functional networks and pathways associated with these gene expression changes.
- To explore the coordination of gene expression in MDD/suicide cases versus controls.
Main Methods:
- Microarray analysis was employed to compare gene expression profiles in brain tissue.
- Pathway analysis was used to identify functional networks among differentially expressed genes.
- Correlational analysis assessed gene expression coordination between groups.
Main Results:
- Differentially expressed genes formed networks related to synapse maturation, neuronal growth, and complexity.
- Validation confirmed that these networks were specific to the MDD/suicide group, not random findings.
- Gene expression was less coordinated in the MDD/suicide group compared to controls.
Conclusions:
- Significant, widespread gene expression perturbations exist in the frontopolar cortex of individuals with MDD who died by suicide.
- These molecular alterations impact critical pathways for synaptic connectivity, neuronal morphology, and cell communication.
- The findings suggest a molecular basis for disrupted brain function in MDD and suicide.
