Scientists have gained new insight into the genetic underpinnings of post-traumatic stress disorder and major depressive disorder through a first-of-its-kind study based on blood samples taken in emergency rooms from patients who had just experienced traumatic events. 

The study, published May 7 in Molecular Psychiatry, identifies a series of possible causal genes for PTSD, bringing us nearer to the long-sought "smoking gun" explaining why some people develop the disorder following a traumatic event, while most others recover after a period of relatively brief psychiatric distress, said Charles B. Nemeroff, a professor of psychiatry, the director of the Institute for Early Life Adversity Research at the University of Texas and the study's corresponding author, in an interview with The Academic Times. 

"If you look at the literature for PTSD, what you find is that even in the most abject trauma, 35% of patients develop the disorder, at most," he said. "The other 65% do not. Fundamentally, the question becomes, 'Can we identify who's at risk for PTSD so that we can focus on those individuals?'"

For the study, research assistants stationed in emergency rooms in Atlanta and Miami assessed more than 10,000 patients, ultimately enrolling over 700 subjects who were seeking medical treatment directly after a traumatic event, such as a physical or sexual assault, a car accident or an animal attack. Interviews were conducted, and blood samples were drawn about 5 ½ hours, on average, after the traumas were experienced. 

"It was technically very difficult because we had to have research assistants in the emergency department 24/7, and most of it happens after 5 o'clock," Nemeroff said. "The strength of the study is in the diversity of trauma and the ability to follow patients over time. This is certainly the largest study that's ever been done in the immediate aftermath of trauma, and the longitudinal nature of the study is also a strength." 

Previous research into the effect of genetic factors on the development of PTSD has usually taken the form of genome-wide association studies, which compare a large sample of people living with a disease and a roughly equal number of control subjects. In such studies, researchers look for genetic variations that could serve as biomarkers for risk in people with the disease, Nemeroff said. Such findings allow researchers to compile risk scores for developing disorders. 

"Historically, what the results have shown is that there are a lot of genes, each of which have a very small effect," he said. "Instead of finding the PTSD gene or the bipolar gene, where it really jumps out as being 1,000 times more prevalent in the disease population, what we find in these studies is 30 genes, each of them contributing a little bit." 

But unlike scientists conducting genome-wide association research, Nemeroff and his colleagues collected blood samples as close to the traumatic event as possible — in addition to assessing the symptoms of 366 participants during a follow-up appointment six months after the traumatic experience — which was critical because gene expression changes on a minute-to-minute basis. "We were interested in whether gene expression in the immediate aftermath of trauma would be related to the development of PTSD, using a much more sensitive measure than the structure of the entire genome," he explained. 

The researchers found a series of genes that could help predict which patients will develop PTSD following trauma: 11 causal driver genes related to major depressive disorder, 13 genes related to PTSD, and 22 genes related to both conditions, which often co-occur. One of the genes that was most abnormally expressed was ESR1, an estrogen-receptor gene, shedding more light on the long-standing mystery of why women are more vulnerable to post-traumatic stress than men are. "There's never been an obvious explanation," Nemeroff said. "But it turns out that estrogen is one of the big drivers of this ESR1 gene expression. That's a pretty big finding." 

Nemeroff has studied trauma for the past 30 years. Over the decades, he has gradually gained a 10,000-foot view of the disease: People who are both predisposed genetically to PTSD and exposed to acute trauma are at higher risk of developing the disorder, while people who don't have a genetic predisposition are relatively resistant to PTSD, even after undergoing similarly traumatizing experiences. While the overall picture is still forming, he said, a more detailed view of the genetic drivers of PTSD could someday help clinicians determine who is most at risk and how to intervene early.  

"For the people with the cardinal symptoms of PTSD, they're suffering terribly," he said. "I saw a patient today who has PTSD as the result of a rape. She can't sleep; when she finally does, she has nightmares. She has flashbacks. She's super vigilant and avoiding any environmental cues that would remind her of the event. It's a terrible disease, and we need to understand why some people develop it and some people don't."

The study, "Integration of peripheral transcriptomics, genomics and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression," published May 7 in Molecular Psychiatry, was authored by Stefan Wuchty, Amanda J. Myers, Manuel Ramirez-Restrepo, Felicia Gould and Philip. D. Harvey, University of Miami; Matthew Huentelman and Ryan Richolt, The Translational Genomics Research Institute; Vasiliki Michopolous, Jennifer S. Steven, Aliza P. Wingo, Adriana Lori, Jessica L. Maples-Keller and Barbara O. Rothbaum, Emory University; Alex O. Rothbaum, Emory University and Case Western Reserve University; Tanja Jovanovic, Wayne State University; Kerry J. Ressler, Emory University and Harvard Medical School; and Charles B. Nemeroff, University of Texas.