Brain transcriptomic signatures for mood disorders and suicide phenotypes: an anterior insula and subgenual ACC network postmortem study

Mood disorders affect over ten percent of humans worldwide. Still, studies dissecting the anatomically localized molecular neurobiological mechanisms underlying mood (dys)functions have not consistently identified the patterns of pathological changes in relevant brain regions. Recent studies have identified pathological changes in the anterior insula (Ant-Ins) and subgenual anterior cingulate (sgACC) brain network in mood disorders, in line with this network's role in regulating mood/affective feeling states. Here, we applied whole-tissue RNA-sequencing measures of differentially expressed genes (DEGs) in mood disorders versus (vs.) psychiatrically unaffected controls (controls) to identify postmortem molecular pathological markers for mood disorder phenotypes. Using data reduction/factor analytics of the postmortem phenotypic variables to determine relevant sources of population variances, we identified DEGs associated with mood disorder-related diagnostic phenotypes by combining gene co-expression, differential gene expression, and pathway-enrichment analyses. We found downregulation/underexpression of inflammatory and protein synthesis-related genes associated with increased psychopathological comorbidity (here referred to as <i>psychiatric morbidity</i>/a measure of all co-occurring mental disorders and death by suicide) in Ant-Ins, in contrast to upregulation of synaptic membrane and ion channel-related genes with increased <i>psychiatric morbidity in</i> sgACC. Our results identified a preponderance of downregulated metabolic, protein synthesis, inflammatory, and synaptic membrane DEGs associated with <i>suicide</i> outcomes, and in relation to a factor representing <i>longevity</i> in the Ant-Ins and sgACC (AIAC) network. Our study revealed a critical brain network molecular repertoire for mood disorder phenotypes, including suicide outcomes and <i>longevity</i>, and provides a framework for defining dosage-sensitive (i.e., downregulated vs. upregulated) molecular signatures for mood phenotypic complexity and pathological consequences.