Cortical Transcriptomic Alterations in Association With Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder

• Published in: The international journal of neuropsychopharmacology Vol. 24; no. 2; pp. 118 - 129
• Main Authors: Stone, Lauren A, Girgenti, Matthew J, Wang, Jiawei, Ji, Dingjue, Zhao, Hongyu, Krystal, John H, Duman, Ronald S
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-02-2021
• Subjects: Adult; Autopsy; Body Mass Index; Cerebral cortex; Complications and side effects; Development and progression; Female; Gene Regulatory Networks - genetics; Genetic aspects; Genetic transcription; Ghrelin - metabolism; Health aspects; Humans; Male; Middle Aged; Neuropeptide Y - metabolism; Obesity; Orexins - metabolism; Physiological aspects; Post-traumatic stress disorder; Prefrontal Cortex - metabolism; Regular; Risk factors; Stress Disorders, Post-Traumatic - metabolism; Transcriptome - genetics; United States; PTSD; transcriptomics; inflammation; BMI
• ISSN: 1461-1457; 1469-5111; 1469-5111
• DOI: 10.1093/ijnp/pyaa072

Abstract
Background
The molecular pathology underlying posttraumatic stress disorder (PTSD) remains unclear mainly due to a lack of human PTSD postmortem brain tissue. The orexigenic neuropeptides ghrelin, neuropeptide Y, and hypocretin were recently implicated in modulating negative affect. Drawing from the largest functional genomics study of human PTSD postmortem tissue, we investigated whether there were molecular changes of these and other appetitive molecules. Further, we explored the interaction between PTSD and body mass index (BMI) on gene expression.
Methods
We analyzed previously reported transcriptomic data from 4 prefrontal cortex regions from 52 individuals with PTSD and 46 matched neurotypical controls. We employed gene co-expression network analysis across the transcriptomes of these regions to uncover PTSD-specific networks containing orexigenic genes. We utilized Ingenuity Pathway Analysis software for pathway annotation. We identified differentially expressed genes (DEGs) among individuals with and without PTSD, stratified by sex and BMI.
Results
Three PTSD-associated networks (P < .01) contained genes in signaling families of appetitive molecules: 2 in females and 1 in all subjects. We uncovered DEGs (P < .05) between PTSD and control subjects stratified by sex and BMI with especially robust changes in males with PTSD with elevated vs normal BMI. Further, we identified putative upstream regulators (P < .05) driving these changes, many of which were enriched for involvement in inflammation.
Conclusions
PTSD-associated cortical transcriptomic modules contain transcripts of appetitive genes, and BMI further interacts with PTSD to impact expression. DEGs and inferred upstream regulators of these modules could represent targets for future pharmacotherapies for obesity in PTSD.