Computational analysis of the divergent neurotranscriptomic signatures of major depression and suicidality

Abstract

Suicide is a leading cause of death globally. Identifying individuals at higher suicidal risk is a key to suicide prevention. Patients with comorbid psychiatric disorders, especially major depressive disorder (MDD), are known to be highly prone to suicidality. However, the behavioural manifestations of MDD and suicidality are distinct, indicating potentially unique molecular underpinnings, of which our current understanding is limited. Delineating the unique and shared molecular etiologies of MDD and suicidality would be imperative to devise effective treatment strategies for suicidal behaviour. To this end, we analysed the existing literature pertaining to transcriptomic alterations in brain samples of individuals who died from MDD or by suicide. Subsequently, biological processes associated with the differentially expressed genes (DEGs) were identified. In addition, we also examined the transcriptional regulators (TRs) potentially driving cortical gene expression changes in MDD and suicidality. A set of immunological genes was found to be commonly upregulated in MDD but downregulated in suicide. Actin and cytoskeleton organization genes also had a similar trend. In addition, MDD-upregulated and suicide-downregulated genes were found to have overrepresented target sites for 40 TRs associated with epigenetic as well as polymerase-mediated regulation. Any variations in the levels of these TRs could be of behavioural consequence in MDD and suicidality. A clear understanding of the condition-specific neurotranscriptomic differences in MDD and suicidality would be valuable in order to delineate the biological mechanisms underlying these conditions. Importantly, it would provide insights into more effective treatment strategies for suicidality among individuals with or without MDD. However, we have yet to determine the molecular basis of suicidality in the context of MDD and as a standalone mental condition. In this regard, the present findings would be of scientific and clinical relevance and could stimulate further research.