ANN ARBOR—University of Michigan researchers say they have identified what appears to be a crucial step in the chain of biological events leading to post-traumatic stress disorder.

Their findings support the idea that exposure to a traumatic event can trigger genetic changes that alter the body’s immune system, leading to post-traumatic stress disorder. PTSD is a severe anxiety disorder that develops in some people who have been exposed to events involving the threat of serious injury or death.

“We think we have uncovered a key biological step in the process that leads to PTSD,” said Monica Uddin, a molecular epidemiologist at the U-M School of Public Health’s Center for Social Epidemiology and Population Health.

“Diseases in general, and psychiatric diseases in particular, involve an interplay between social and biological factors,” said Uddin, an assistant research scientist in the U-M Department of Epidemiology and lead author of a paper scheduled to be published online Monday in the Proceedings of the National Academy of Sciences.

“In the case of PTSD, traumatic events can get under your skin and literally alter your biology, with significant physical and mental consequences,” she said. “That’s the main message of this paper.”

The researchers used data from the Detroit Neighborhood Health Study, a five-year project funded by the National Institutes of Health. They examined more than 14,000 genes using DNA from blood samples provided by 100 Detroit residents. Twenty-three of those individuals suffered from post-traumatic stress disorder.

The researchers identified numerous genes?most of them involved in regulating the immune system?that appeared to be more active in people with PTSD. Previous studies have posited a link between altered immune function and PTSD. The new U-M findings support that model and go a step further by identifying a specific biochemical reaction that may be involved.

That biochemical reaction is a process called DNA methylation, in which methyl groups (CH3 groups) are added to some of the molecular letters that spell out the genetic code. DNA methylation can alter gene activity, typically reducing it.

For technical reasons, the U-M-led research team could not directly measure gene activity in this study. So they used methylation patterns as a proxy for gene activity and compared the signatures found in PTSD sufferers to those without the disorder.

They found that methylation levels of immune-related genes were lower in the PTSD group, suggesting increased activity in those genes. That finding supports a model for PTSD in which exposure to a traumatic event changes gene expression, which in turn alters immune-system activity, leading to the disorder.

“To the best of our knowledge, there have been no studies to date that have documented differences in epigenetic methylation patterns among persons with vs. without PTSD,” the authors wrote.

The findings have potential implications for the treatment of PTSD. Since DNA methylation states are changeable, it’s conceivable that genes identified in this study could become targets for new drug therapies to treat PTSD, Uddin said.

In a follow-up project that’s part of the Detroit Neighborhood Health Study, the researchers will analyze blood samples from about 500 Detroit residents. They’ll test DNA methylation levels again, and they’ll also directly measure gene activity by analyzing RNA in the blood samples. The follow-up study is funded, in part, by a $995,000 Challenge Grant from the National Institutes of Health.

Allison Aiello, an assistant professor of epidemiology at the School of Public Health, is the principal investigator for the Challenge Grant. In addition, Aiello took over as leader of the Detroit Neighborhood Health Study after Sandro Galea left U-M for Columbia University.

In addition to Uddin, Aiello and Galea, the authors of the PNAS report are Derek Wildman of Wayne State University, Karestan Koenen of the Harvard School of Public Health, Graham Pawelec of the University of Tubingen Medical School in Germany, Regina de los Santos of the University of Michigan and Emily Goldmann of the University of Michigan.

The study was supported by several National Institutes of Health grants. Additional support was provided by the Robert Wood Johnson Health and Society Scholars Small Grant Program, the U-M Office of the Vice President for Research Faculty Grants and Awards Program, the Wayne State University Research Excellence Fund, and a grant from the U-M Nathan Shock Center.

Detroit Neighborhood Health Study