Newswise — Stress-related disorders stem from the interplay of genetic susceptibility and stress exposure, shaping gene and protein expression through epigenetic modifications across the lifespan. Studies on postmortem brains of post-traumatic stress disorder (PTSD) and major depression (MDD) patients, compared to neurotypical controls, have revealed genetic overlap, sex differences, and immune and interneuron signaling involvement, yet lack integrative analyses.
To address this gap, Yale scientists established a brain multi-omic, multi-region analysis comprising individuals with PTSD, MDD, and neurotypical controls. The results of their work .
The scientists measured molecular changes across the human dorsolateral prefrontal cortex and subgenual anterior cingulate cortex at genetic, transcriptional, post-transcriptional, and proteomic levels. They found differentially expressed proteins and co-expression protein modules disrupted by PTSD.
Integrative analysis with RNA and small non-coding RNA datasets from the same cohort pointed to the microRNA hsa-mir-589 as an upstream regulator responsible for dysregulation of neuronal protein networks including the GABA transporter, SLC32A1.
In addition, they identified significant enrichment of risk genes for other psychiatric disorders, such as depression, autism, and bipolar disorder within PTSD protein networks, suggesting shared molecular pathology.
“This study represents a first systems biology approach for PTSD and major depression using postmortem brain genomics,” said Matthew Girgenti, PhD, assistant professor of psychiatry and the paper’s senior author.
“Our approach unveiled shared and unique brain multi-omic molecular dysregulations in PTSD and MDD, elucidating distinct cell-type involvement and paving the way for biomarker development,” he said. “These insights not only implicate established stress-related pathways but also offer potential therapeutic avenues.”
Other Yale investigators include members of the Yale NIDA Neuroproteomics Core; Angus Nairn, PhD; Kenneth Williams, PhD; TuKiet Lam, PhD; and Marina Picciotto, PhD.
The research reported in this news article was supported by the Department of Veterans Affairs, National Center for PTSD, Brain and Behavior Research Foundation, American Foundation for Suicide Prevention, Yale/NIDA Neuroproteomics Center (NIHDA018343), National Institutes of Health National Institute on Drug Abuse, and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
RSS