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New Genetic Clues to Posttraumatic Stress Disorder

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.

Feb. 23, 2011 -- 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.”

The study is published in the journal Nature.

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.

When they tested 798 traumatized people, they found that women, but not men, diagnosed with PTSD were far more likely to carry a certain variant of the PACAP receptor gene than those who were not.

And they couldn’t figure out why it was only turning up in women.

“So we were scratching our heads about that for a while,” Ressler says.

Until they looked more closely and saw that the region of the gene where the variant was located sat squarely in the middle of something called an estrogen response element, or a piece of DNA that gets switched on by the hormone estrogen.

“We just couldn’t believe it,” Ressler says. “This is one of the stories in science that you kind of live your career for. Where every time you looked at something it continued to go in the same direction in a robust way and make more and more sense.”

What Ressler and his team had, they knew, was an exciting correlation between two things, the PACAP receptor and higher rates of PTSD in their study participants, but they didn’t have any proof that one caused the other.

So they went further, experimentally startling study participants by hitting them with a blast of air or sounding a loud noise in the dark. Those who reacted most strongly were the more likely to carry the genetic variant for the PACAP receptor than those who didn’t startle as easily.

Then they tested their theory in animals. They removed the ovaries from rats and then replaced the lost estrogen in some of the animals but not others. After a few weeks, the rats exposed to estrogen had more of the peptide receptor genes than those who did not.

And in mice, they measured the levels of the PACAP receptors in the brains of the mice that were conditioned to respond to fear. After being exposed to fear, there were more PACAP receptors in their brains.

How Common Is the Gene?

In their traumatized population, Ressler says about 30% to 40% of people turned out to have at least one copy of the variant PACAP receptor gene and about 15% had two copies, a finding that indicates that inheriting the gene for this version of the PACAP receptor doesn’t make PTSD a given.

“In no way is this causal,” Ressler explains. “But it may help to divide risk vs. resilience.”

Ressler thinks PACAP is probably acting in concert with other genes in PTSD.

“It’s not the whole story,” he says. “We think it’s going to be one of a handful of these genes that together are acting on these pathways.”

One of the next steps, he says, will be trying to block the action of the receptor, perhaps with a drug, to see if they can expose animals to fear without giving them PTSD.

If that works, it may be the first step in the development of new treatments for the disorder, which often causes terrifying flashbacks, nightmares, depression, anxiety, memory problems, difficulty concentrating, numbness, and anger.

“The fear circuits in the brain are very highly conserved from humans all the way down to mice,” Ressler says. “So I personally think we’re going to understand the neurobiology of PTSD much faster than we do many other disorders, so for me, I certainly want to help come up with that.”

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