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, but studies dissecting the brain anatomical and 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 networks 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-driven factor analysis 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/under expression of inflammatory, and protein synthesis-related genes associated with psychiatric morbidity (i.e., all co-occurring mental disorders and suicide outcomes/death by suicide) in Ant-Ins, in contrasts to upregulation of synaptic membrane and ion channel-related genes with increased psychiatric morbidity in sgACC. Our results identified a preponderance of downregulated metabolic, protein synthesis, inflammatory, and synaptic membrane DEGs associated with suicide outcomes in relation to a factor representing longevity 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 longevity, and provides a framework for defining dosage-sensitive (i.e., downregulated vs. upregulated) molecular signatures for mood disorder phenotypic complexity and pathological outcomes.