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

Abstract

Maintaining a balanced mood state is necessary for human well-being and survival. Several brain changes, including reduced anatomical integrity identified in imaging studies and molecular measures of transcriptomic changes identified in postmortem brain RNA-sequencing (RNA-Seq) studies, have been found in major depressive disorder (MDD) and bipolar disorder (BD) (here referred to as mood disorders). Although the human anterior insula (Ant-Ins) and subgenual anterior cingulate (sgACC) are involved in the regulation of mood/affect, and feeling states, studies dissecting the molecular neurobiological mechanisms of mood (dys)functions have not consistently targeted this critical brain network. Here, we studied the postmortem Ant-Ins and sgACC and applied whole-tissue RNA-seq measures of differentially expressed genes (DEGs) in mood disorders versus (vs.) psychiatrically unaffected controls (controls). We identified DEGs associated with mood disorder-related diagnostic phenotypes by combining gene co-expression, differential gene expression, and pathway-enrichment analyses. Using factor analysis of the postmortem phenotypic variables to determine relevant sources of population variances, we identified 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. We further 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 network. Our findings revealed a critical brain network molecular repertoire for mood disorder phenotypes, including suicide outcomes and longevity. This work provides a framework for studying directionally defined (downregulated vs. upregulated) molecular mechanisms for mood disorder phenotypic complexity and disease outcomes.