An international team of researchers says it has found a gene and its associated protein that appears to play a key role in how well women withstand stress and fear, which may influence the development of posttraumatic stress disorder (PTSD) after a stressful event.

The protein, known as pituitary adenylate cyclase-activating polypeptide (PACAP), appears to be controlled by estrogen, which may help explain why women have far higher rates of PTSD than men.

If the research can be duplicated, the discovery may one day lead to new tests and treatments for the disabling disorder, which studies indicate may affect as many as one in 10 women.

“Anytime we find something strong biologically, in a mental health-related issue, it’s important because it helps remind everyone - from the patients to the doctors to the insurance companies - that these are real biological diseases,” says study researcher Kerry Ressler, MD, PhD, an associate professor in the department of psychiatry and behavioral sciences at Emory University in Atlanta.

Researchers who were not involved in the study praised its comprehensiveness and called its conclusions tantalizing. “The findings that are reported are extremely interesting and potentially very exciting,” says Ned H. Kalin, MD, the Hedberg Professor and Chair of Psychiatry at the University of Wisconsin, Madison. “It’s potentially a new lead from the standpoint of understanding the molecular underpinnings of stress-related psychopathology.”

“The cautionary note is that, more and more, we’re learning that most psychiatric illnesses are determined by multiple genes and environmental factors interacting and that each of the genes involved is contributing just a little bit to the risk,” says Kalin, who is studying the genetic underpinnings of anxiety. “And so while this looks like it’s an important lead, it shouldn’t be misconstrued as the only thing, as a silver bullet.”
A Biomarker for PTSD

In an impressive bit of scientific detective work, Ressler and colleagues first took blood and saliva samples from 1,200 men and women who had experienced trauma in an inner-city environment. Examples of those traumas were shootings, gang or drug-related violence, or rape, Ressler says.

They cross-referenced genes and proteins found in those samples with genes and proteins that were amplified in the brains of mice that were exposed to fear.

“The PACAP receptor was the very top of the list when we combined both gene sets,” Ressler says.

When they tested for PACAP in the blood samples from their traumatized patients, they found that women with high levels of this protein were more likely to have PTSD than those who had lower levels, but there was no such association in men.

So in the next round of sleuthing, they looked at the specific genes that code for PACAP and its receptor, a kind of docking station that allows a signaling protein to attach to a cell and deliver its instructions.