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Study links gene to PTSD risk

thumbnail Shedding light on PTSD—In the first published results from a genome-wide association study on posttraumatic stress disorder, a team with VA and Boston University describe a gene variant that may increase risk for the condition. Research on U.S. troops who have served in Iraq and Afghanistan suggests 10 to 18 percent are likely to have PTSD after they return home. (Photo by Sgt. Kimberly Trumbull)

Based on DNA analysis on hundreds of trauma-exposed Veterans and other volunteers, researchers with VA and Boston University have pinpointed a gene variant they say substantially increases the risk of posttraumatic stress disorder. The discovery could eventually help guide PTSD care.

The findings, now online in Molecular Psychiatry, are the first published results from a genome-wide association study on PTSD.

Senior author Mark Miller, PhD, says the new finding is preliminary but very promising. "I'm optimistic that we're onto something real." He says the results may lead to a better understanding of exactly what goes awry in the brain in PTSD, and aid in the development of new drugs and diagnostic or preventive measures.

Miller is a clinical and research psychologist with the Behavioral Sciences Division of VA's National Center for PTSD, and an associate professor at Boston University School of Medicine.

In a genome-wide association study, or GWAS, researchers scan the entire genetic material of a person—all his or her DNA. They use chips that contain probes for millions of possible gene variants. The goal is to pinpoint variants that are more common in people with a certain disorder than in those without it.

The Boston study, which included more than 500 Veterans—many of them with combat trauma—homed in on the retinoid-related orphan receptor alpha (RORA) gene and one of its variants, rs8042149. The variant is a single nucleotide polymorphism, or SNP. In simpler terms, it is a change in one of the chemical bases that make up the gene. One gene can potentially have up to thousands of such variants.

Most published studies to date on the genetics of PTSD have been "candidate gene studies." In these studies, researchers first sift though biomedical evidence to identify genes that appear to be involved in a certain health condition. They then examine those specific genes in patients' DNA and look for variants that may be associated with the disease. The focus, says Miller, is only on "the usual suspects"—genes known to play a role in that area of health. Such research often follows "knock-out" studies in mice, in which scientists genetically engineer the lab animals to lack a certain gene and then observe the effects on health and behavior.

In a GWAS, in contrast, researchers start with no set idea of which gene will emerge as a marker of the condition. The human genome contains some 23,000 protein-coding genes in all.

"You just look at the data," says Miller. "It's more of a discovery approach. You can come up with a finding anywhere in the genome." He adds that since most of the genome is still an unknown—uncharted territory—and scientists know little about the role of various genes and other pieces of DNA, "chances are you're going to find an association in an area of DNA whose function you have no idea about."

The psychologist says his team was "particularly excited" when they realized that the RORA gene pinpointed in their study has been the focus of other recent research on mental health conditions. It's been implicated in attention deficit hyperactivity disorder, bipolar disorder, autism, and depression, which frequently accompanies PTSD. The gene is known to affect brain development, neuroprotection (protection of brain cells from injury or degeneration), and hormone production.

On a basic level, says Miller, the gene "detects changes in the biochemical cellular environment and responds to those changes." He and his coauthors believe changes in RORA may lead, in essence, to a meltdown on the part of brain cells when the stress level rises. In their article, the researchers wrote that the particular gene variant their study homed in on, rs8042149, may "reduce the capacity of neurons to respond to the biochemical stressors induced by traumatic stress," such as elevated hormone levels, inflammation, and free-radical damage.

"Our theory is that for people who have the RORA risk variant, their neurons are less able to mount a defense against the damaging effects of stress on the brain," Miller explains.

He cites further evidence bolstering a possible link between PTSD and RORA. For starters, the gene codes for proteins found in brain regions that help with emotional regulation and behavioral control, such as the hippocampus, anterior cingulate cortex, and prefrontal cortex. And at least one study has linked RORA expression levels to the thickness of the brain's white and gray matter. Interestingly, brain scans of those with PTSD have also found reduced volume in certain brain areas, including the hippocampus. One theory is that the volume shrinks in response to trauma and the chronic stress that follows. Another is that people who inherently have less volume in those areas may be more susceptible to PTSD in the wake of trauma.

Either way, Miller's team is eager to further explore the RORA-PTSD link. "We hope to connect with colleagues doing structural imaging," he says. One tentative plan is to work with VA researchers at the Boston-based Translational Research Center for TBI and Stress Disorders. One of the questions to be answered: Will Veterans with PTSD who have the "rs8042149" variant show signature patterns of structural brain changes?

The group will also look at other RORA variants that may play a role. The probe-containing chip they used in their GWAS tests for only 600 or so RORA variants. "There are actually thousands of potential variants of the gene that could be tied to PTSD," says Miller. The researchers have their work cut out for them, but having a focus on a particular gene may pave the way for future progress.

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