For years, researchers have struggled to understand the underlying biology of fear. Why do terrifying situations cause deep and lasting damage in some people, while others may emerge from the same event shaken but essentially unharmed psychologically? Being able to predict who might be vulnerable to conditions such as post-traumatic stress disorder (PTSD) has remained an elusive goal. Now, a Howard Hughes Medical Institute (HHMI) scientist has identified a genetic marker that appears to predict a diagnosis of PTSD in women but not in men.

PTSD is not limited to soldiers who have seen combat--more than 7 million people in the U.S. suffer from the disorder, and a woman’s risk of developing PTSD may be twice that of a man’s. HHMI investigator Kerry Ressler and colleagues at Emory University and the University of Vermont have discovered that women with PTSD have high levels of a protein called pituitary adenylate cyclase activating polypeptide (PACAP) in their blood. Furthermore, a particular genetic mutation in the PACAP receptor gene also associates with PTSD risk in women. The preliminary results, reported in the February 24, 2011, issue of the journal Nature, could lead to the first blood test for susceptibility to PTSD and a better understanding of how to treat it.

“Understanding biomarkers and the biological mechanisms of psychological disorders is critical for prediction, understanding, and treatment of disorders such as PTSD.”
Kerry J. Ressler

Ressler and others in the field have struggled to identify reliable biomarkers – substances or biological compounds – that would help them predict a person’s susceptibility to specific psychiatric disorders. “There remain no reliable biomarkers for most psychiatric disorders,” says Ressler, an associate professor of psychiatry and behavioral sciences at the Yerkes National Primate Research Center and Emory University in Atlanta. “Understanding biomarkers and the biological mechanisms of psychological disorders is critical for prediction, understanding, and treatment of disorders such as PTSD.”

Ressler and his collaborators initially used blood samples from a small group of 64 men and women who were part of a highly traumatized population known to be at risk for PTSD. When they compared the level of PACAP in the study’s subjects, they found that women who had been diagnosed with or had symptoms of PTSD had higher levels of the peptide than women who had not been diagnosed with the disorder. But there was no association of PACAP levels with PTSD symptoms in men. A replication study focused on 74 additional traumatized women and also showed a clear association between those who had high PACAP levels and those who had signs of PTSD -- symptoms such as flashbacks to traumatic events, avoiding things that reminded them of the trauma, and physical indications of stress such as an increased startle response.

“When we started this, we did not expect to see sex differences,” Ressler says. “But in retrospect, it makes some sense.” When the scientists looked at the underlying genetics in a larger population of more than 1200 at-risk individuals, they found a single nucleotide polymorphism or mutation that was associated with the presence of PTSD. The mutation appeared in a region of the PACAP receptor gene that is directly responsive to estrogen regulation. “Estrogen has been shown to alter the fear response in earlier literature. So one possible mechanism for this may be through the PACAP system,” Ressler says.

To test their findings in animals, the researchers removed the ovaries from a group of female rats. This step ensured that the rats could not produce their own estrogen. Half of the rats were then given estrogen supplements, while the other half remained estrogen-free. The researchers found that the animals that had received estrogen replacements showed a significant increase in PACAP gene activity in areas of the brain that mediate fear, stress, and estrogen response. In an additional animal study, mice were trained to associate fear with specific auditory stimuli. During the period following the training, when the fear memories are encoded within the brain, there was an increase in PACAP receptor gene activity in the amygdala, the part of the brain most responsible for fear responses.

“These findings tell us that, like many complex medical diseases, a traumatized person can arrive at PTSD in different ways. PTSD and other psychiatric disorders probably share common pathways of brain dysfunction, and I think we’re going to find that there are lots of ways to get there,” Ressler says. Just as child abuse or high levels of prior trauma can increase risk, he says, “it appears that sex hormones are also going to be one of the many mediators that leads you down one path versus a different path in terms of risk.”

The PACAP pathway is a new one for PTSD researchers, and one that bears close attention, Ressler says. “If this is replicated in larger samples, it may serve as a biomarker for PTSD. The more molecular tools we have to identify patients’ differential risk, the better we’ll be able to understand the pathogenesis of the disorder and to make predictions of trauma response, risk and treatment.” Not only that, but if researchers could create a way to block the PACAP receptors, the results could lead to a potential new drug treatment for PTSD.

Ressler hopes to follow up on these findings to see how they apply to larger populations of both civilians and veterans alike, and also plans to study the genetics of 14,000 traumatized civilians, which will be the largest genomic study of PTSD to date.