In studying psychiatric disorders, researchers must account for both the environmental and biological components that may play into a condition’s presentation. In post-traumatic stress disorder (PTSD), the environmental component is written into the name—trauma. But much still needs to be uncovered surrounding the biological mechanisms, which was the goal of an article published in Nature Neuroscience in January of this year, led by researchers in the Department of Psychiatry at the Yale School of Medicine. Researchers dove into the transcriptomic organization of postmortem tissue in the PTSD-diagnosed brain, meaning they analyzed the collection of messenger RNA (mRNA) transcripts present in a cell—known as the transcriptome—to understand the molecular mechanisms underlying this disorder. This investigation illuminated sex differences in PTSD expression, unexpected correlations with other disorders, and several genes of interest in the pathophysiology of PTSD.
The paper homed in on four subregions of the prefrontal cortex (PFC), a region of the brain highly implicated in emotion regulation, chosen because of previously observed differences between PTSD patients and healthy patients in this area. Not unlike other psychiatric conditions, PTSD does not have a clear-cut cause. A range of trauma types can contribute to its emergence and may even have an impact at the molecular level. “We would predict differences in molecular profiles for different traumas,” said Matthew Girgenti, a research scientist at the Yale School of Medicine. “I do think that the trauma type has an effect on how and when you develop PTSD,” Girgenti said, bringing to light the complex interplay of environmental and biological factors. This interplay may also be present in sex differences in PTSD, as the traumas that most often lead to PTSD diagnoses in men and women are vastly different, the former being combat trauma and the latter being sexual trauma.
Researchers found that sex, in fact, had the greatest effect on molecular variance in PTSD. All subregions of the PFC displayed transcriptomic differences between men and women, with women additionally showing more differentially expressed genes (DEGs) between the PTSD and control groups. The identified genes are involved in GABAergic signaling, which is significant given that GABA serves as a major inhibitory neurotransmitter implicated in traumatic stress. One of these genes, ELFN1, was identified as a key player in the observed sex differences. ELFN1 was significantly downregulated, meaning there was significantly less of the transcript in PTSD patients in females but not in males. Another key gene, UBA7, also showed sex differences and was downregulated in multiple subregions. This gene is involved in inflammatory and immune processes, which have been implicated in the pathophysiology of many psychiatric disorders.
Another goal of this research was to explain on a molecular level the high comorbidity, or simultaneous presence, of PTSD and major depressive disorder (MDD). Surprisingly, despite nearly fifty percent of newly diagnosed PTSD patients having comorbid MDD, their transcriptomic profiles were found to be quite dissimilar. While there were a high number of DEGs present in the PFC regions of MDD brains, the overlap with PTSD was minimal. The researchers identified one gene, GADD45B, that PTSD and MDD brains had in common across both sexes; GADD45B therefore serves as a molecular intersection between these two disorders. Overall, however, the results indicate a non-significant overlap, and the researchers concluded that these disorders are more dissimilar than previously thought.
So, what can explain the high tendency for PTSD and MDD to occur together? “PTSD is still stress, and any amount of stress can lead to some type of depression,” Girgenti said. “Having PTSD makes you prone to many comorbidities including depression.” Interestingly, the PTSD transcriptome did significantly correlate with other neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder, implicating that the molecular pathologies of these disorders overlap to some degree.
This research demonstrates important progress in our understanding of the molecular mechanisms involved in PTSD and how these may interact with sex and other diagnoses. Unfortunately, there are currently no medications specifically designed to treat PTSD. However, the gene networks identified here may play an important role in developing a treatment. “Therapeutically targeting those systems [GABAergic and inflammatory] is most likely to succeed,” Girgenti said. “We hope to identify genomic targets that are changing in PTSD and find current drugs we can repurpose to target those.” The genomic landscape of the PTSD brain brought to light by this research may have important implications for therapeutic interventions as well as for gaining a deeper understanding of the impact of traumatic stress on the brain.
Girgenti, M. J., Wang, J., Ji, D., Cruz, D. A., Alvarez, V. E., Benedek, D., Brady, C., Davis, D. A., Holtzheimer, P. E., Keane, T. M., Kowell, N., Logue, M. W., McKee, A., Marx, B., Mash, D., Miller, M. W., Scott, W. K., Stein, T., Ursano, R., … Duman, R. S. (2021). Transcriptomic organization of the human brain in post-traumatic stress disorder. Nature Neuroscience, 24(1), 24–33. https://doi.org/10.1038/s41593-020-00748-7
National Human Genome Research Institute. (2020, August 17). Transcriptome fact sheet. Retrieved from https://www.genome.gov/about-genomics/fact-sheets/Transcriptome-Fact-Sheet