Neuro-transcriptomic signatures for mood disorder morbidity and suicide mortality

Abstract

Suicidal behaviors are strongly linked with mood disorders, but the specific neurobiological and functional gene-expression correlates for this linkage remain elusive. We therefore tested the hypothesis that a convergent neuroanatomical and gene-expression signature will underlie mood disorder associated psychiatric morbidity and related suicide mortality. To do so, first, we applied an anatomical likelihood estimation (ALE) MRI meta-analysis across 72 voxel-based morphometry (VBM) studies including 2387 (living) participants that identified a selectively reduced anterior insula cortex gray matter volume (GMV) as a potential neuroanatomical signature for mood disorder. This neuroanatomical signature was then specifically used to guide postmortem RNA-Sequencing studies of 100 independent donor brains with a life-time history of major depressive disorder (N=30), bipolar disorder (N=37) and non-affected controls (N=33) using a sample from the National Institute of Mental Health Brain collection core. In this latter study, factor analysis first identified a higher-order factor representing number of Axis-1 diagnoses (i.e. morbidity) and suicide-completion (i.e. suicide-mortality). Using this higher-order factor as a contrast variable, differential gene-expression changes were examined in high psychiatric morbidity and related suicide mortality versus low psychiatric morbidity and related suicide mortality in mood disorder cohorts and controls. We identified in immune, inflammasome, neurodevelopmental, and transcriptional pathways and a weighted gene coactivation network analysis identified co-activated gene modules for psychiatric morbidity and suicide-mortality outcomes. These results provide a functional gene-expression link between mood disorder associated psychiatric disease morbidity and suicide-mortality.

Transcription factor motifs associated with anterior insula gene-expression underlying mood disorder phenotypes

“…JASPAR 2018 TFs binding profiling: Given the role of transcription factors (TFs) in regulating gene expression via specific DNA-binding domains (motifs) in the gene promoters, we followedup on our previous study (Jabbi et al 2020) that identified whole transcriptome gene expression profiles in mood disorders, with the aim to explore in more detail, mood disorder transcriptomics by identifying TF motifs. To this goal, we used JASPAR TF binding database to identify motifs that were associated with DEGs in BD vs. controls; MDD vs. controls, and in pooled mood disorder individuals with high vs. low Axis-I comorbidity.…”

“…Using the anatomical likelihood estimation meta-analysis (Eickhoff et al 2009), we previously identified the right anterior insula as the brain region with the most extensive GMV reduction in mood disorders relative to healthy controls ( Figure. 1A) (Jabbi et al 2020). We manually reconstructed this region in ITKSnap (http://www.itksnap.org/pmwiki/pmwiki.php) and provided this 3-D volume information to the pathologist at the brain bank to guide postmortem dissection of anterior insula tissue from each sample for subsequent RNA extraction and RNA-sequencing.…”

“…TFs are known to regulate expression of toll-like receptor signaling genes, cellular homeostatic control genes, and genes involved in embryonic, cellular and neurodevelopmental processes. In the present study, we applied robust imaging-guided transcriptomics to target neuroimaging identified GMV reductions in the anterior insula associated with mood and depressive disorder diagnoses (Goodkind et al 2015;Jabbi et al 2020) for dissection and subsequent RNA-seq analysis in postmortem donors. This novel approach allows the precise molecular targeting of a localized anterior insula region that has been found to exhibit the strongest degree of gray matter loss in mood disorders (Jabbi et al 2020).…”

“…In the present study, we applied robust imaging-guided transcriptomics to target neuroimaging identified GMV reductions in the anterior insula associated with mood and depressive disorder diagnoses (Goodkind et al 2015;Jabbi et al 2020) for dissection and subsequent RNA-seq analysis in postmortem donors. This novel approach allows the precise molecular targeting of a localized anterior insula region that has been found to exhibit the strongest degree of gray matter loss in mood disorders (Jabbi et al 2020). This robust imagingguided transcriptomics study therefore integrated RNA-seq characterization of gene expression abnormalities in an anatomically abnormal region in mood disorders and allowed testing of the hypothesis that transcription factor motifs will be associated with differential gene expression profiles in the postmortem anterior insula cortex of mood disorder subjects relative to controls.…”

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