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.