A multi-omic approach implicates novel protein dysregulation in post-traumatic stress disorder microbiologystudy

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 are published in Genome Medicine.

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, Ph.D., 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.”