Integrative genome-wide gene expression and DNA methylation analysis in brain tissue from medication-free suicide decedents and their controls

Abstract Suicide rates have increased steadily world-wide over the past two decades, constituting a serious public health crisis that creates a significant burden to affected families and the society as a whole. Suicidal behavior involves a multi-factorial etiology, including psychological, social and biological factors. Since the molecular neural mechanisms of suicide remain largely uncharacterized, we examined transcriptional- and methylation profiles of postmortem brain tissue from subjects who died from suicide as well as their neurotypical healthy controls. We analyzed temporal pole tissue from 61 subjects, free from antidepressant and antipsychotic medication, using whole genome RNA-sequencing and DNA-methylation profiling using an array that targets over 850,000 CpG sites. Expression of , a key regulator of inflammation and neuroprotection, was significantly downregulated in the suicide-decedent group. Moreover, we identified a total of 40 differentially methylated regions in the suicide decedent group, mapping to seven genes with inflammatory function. There was a significant association between DNA methylation and expression in the control group that was absent in the suicide decedent group, confirming its dysregulation. expression was significantly associated with the expression of multiple inflammatory factors in the brain tissue. Overall, gene sets and pathways closely linked to inflammation were significantly upregulated, while specific pathways linked to neuronal development were suppressed in the suicide decedent group. Excitotoxicity as well as suppressed oligodendrocyte function were also implicated in the suicide decedents. In summary, we have identified central nervous system inflammatory mechanisms that may be active during suicidal behavior, along with oligodendrocyte dysfunction and altered glutamate neurotransmission. In these processes, NPAS4 might be a master regulator, warranting further studies to validate its role as a potential biomarker or therapeutic target in suicidality.