ABSTRACT
Background Mood disorders represent a major cause of morbidity and mortality worldwide but their pathophysiology remains obscure. Gene expression profiles, especially with regards to the interactive influence of genes within the expression profiles underlying pathological brain phenotypes associated with mood disorders remains largely undefined.
Methods Because the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from postmortem mood disorder samples and compared with unaffected control samples for RNA-sequencing identification of differentially expressed genes (DEGs) in a) bipolar disorder (BD; n=37), and b) major depressive disorder (MDD n=30) vs controls (n=33), and c) low vs high Axis-I comorbidity (a measure of psychiatric morbidity burden). Given the regulatory role of transcription factors (TFs) in gene expression via specific-DNA-binding domains (motifs), we used JASPAR TF binding database to identify TF-motifs.
Results We found that DEGs in BD-vs-controls, MDD-vs-controls, and high-vs-low Axis-I comorbidity burden were associated with TF-motifs known to regulate expression of toll-like receptor signaling genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular, organ and brain developmental processes.
Discussion Robust image-guided transcriptomics was applied by targeting the gray matter volume reduction in the anterior insula in mood disorders, to guide independent postmortem identification of TF motifs regulating DEG. TF motifs were identified for immune, cellular, embryonic and neurodevelopmental processes.
Conclusion Our results provided novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.
Competing Interest Statement
Competing Interests: Mbemba Jabbi, none. Dhivya Arasappan, none. Simon Eickhoff none. Hans Hofmann, none. Charles B Nemeroff: Research/Grants: National Institutes of Health (NIH) Consulting (last three years): Xhale, Takeda, Taisho Pharmaceutical Inc., Signant Health, Sunovion Pharmaceuticals Inc., Janssen Research & Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., TC MSO, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Gerson Lehrman Group (GLG), Acadia Pharmaceuticals Stockholder: Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Antares, BI Gen Holdings, Inc., Corcept Therapeutics Pharmaceuticals Company, TC MSO, Inc., Trends in Pharma Development, LLC, EMA Wellness Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc. Board of Directors: Gratitude America, ADAA, Xhale Smart, Inc. Income sources or equity of $10,000 or more: American Psychiatric Publishing, Xhale, Signant Health, CME Outfitters, Intra-Cellular Therapies, Inc., Magstim, EMA Wellness Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1) Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2) Compounds, Compositions, Methods of Synthesis, and Methods of Treatment (CRF Receptor Binding Ligand) (US 8,551, 996 B2) Speakers Bureau: None
Footnotes
Additional analysis, results, and clarifications were included and the manuscript is currently resubmitted for peer review.