Veterans posted to Iraq and Afghanistan have a much higher risk of suicide than the general US population and far higher than seen in veterans from earlier wars.Photo credit: US Navy photo by Mass Communication Specialist 3rd Class Anna Van Nuys/ReleasedThe statistics are grim. Veterans of the conflicts in Iraq and Afghanistan have a 41 to 61 percent higher risk of suicide than the general US population, according to a 2014 study in the Annals of Epidemiology. This risk is far higher than seen in veterans from earlier wars, so high that the US Senate and the House of Representatives unanimously passed a bill in early 2015 to improve suicide prevention programs at the US Department of Veterans Affairs (VA).

The suicide risk is “alarmingly high,” says Naomi Sadeh, a Boston University School of Medicine assistant professor of psychiatry and a psychologist at the National Center for PTSD. And the numbers raise important questions for researchers: which veterans will turn to suicide, and why? While risk rises for many reasons, PTSD (post-traumatic stress disorder) has emerged as one of the strongest predictors. But “not every veteran develops PTSD or becomes suicidal,” says Sadeh. “Our biggest challenge right now is predicting who is going to attempt suicide—we’re not really very good at that yet.”

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Sadeh is lead author on a September 2015 study in Molecular Psychiatry pointing to a biomarker that might bring researchers a little closer to the goal of better predicting—and perhaps treating—PTSD and suicide risk: a gene called SKA2. Biomarkers, short for “biological markers,” are measurable indicators of health or disease, things like blood cholesterol or antibody levels. Many biomarkers don’t provide a definitive diagnosis of disease, but in conjunction with other health information, can indicate risk, and also possible avenues of treatment. Scientists across disciplines are actively searching for biomarkers that may indicate early signs of diseases like Alzheimer’s, Parkinson’s, lung cancer, and in this case, risk of suicide. “In the past, we’ve relied on self-reporting to estimate suicide risk: veterans telling us when they have depression or symptoms of PTSD,” says Sadeh. “The field is looking for more objective measurements, and that’s where biomarkers come in.”

“At first I was skeptical about trying to find a genetic association for anything as complicated as suicide risk, because there are so many factors that go into it,” says Mark Miller, a MED associate professor of psychiatry and senior author on the study, whose work is supported by the National Institute of Mental Health and the VA. “But within the last few years researchers have made many advances in identifying molecular markers that may be linked to suicide.”

SKA2 emerged as a possible biomarker for suicide risk in 2014, when researchers from Johns Hopkins compared the brains of people who had died from suicide to those who died from other causes. When screening the genomes of people who had died from suicide, the researchers looked for genes that were methylated—tagged with a tiny molecule of one carbon and three hydrogen atoms known as a methyl group—differently than in other genome samples. Methylation is one of the primary ways that the body (or the environment) switches genes on and off. The Johns Hopkins group found that in the brains of people who had died from suicide, the SKA2 gene was methylated in a certain location and thereby switched off. That study, published in the American Journal of Psychiatry in 2014, also found the same changes in SKA2 in the blood of live patients experiencing suicidal thoughts.

MED researchers Mark Miller and Naomi Sadeh study whether genetic changes may lead to a heightened risk of suicide in veterans.Photo credit: Cydney ScottAlthough researchers still aren’t sure exactly what role SKA2 plays in the body, or why turning it off might increase risk for suicide, studies have shown that it helps regulate the HPA (hypothalamic-pituitary-adrenal) axis, a hormonal system that plays a role in our fight-or-flight response and other reactions to stress. Early research indicates that the SKA2 protein protects brain cells from damage, and that when the gene is turned off, stress hormones in the brain can cause cell damage and death.

The Hopkins study turned a spotlight on SKA2 and caught the eye of Miller and Sadeh. “It was a great study,” says Sadeh, “but one limitation was that it didn’t look at the brains of living individuals. So we wondered if we could bridge the gap between postmortem brains and living people.”

To cross this divide, Sadeh examined data from the VA’s Translational Research Center for TBI and Stress Disorders database, which contains health information—including brain scans, blood tests, and the results of comprehensive psychological exams—from about 200 veterans who have faced trauma. By analyzing the data, she found that methylated SKA2 was associated with more severe symptoms of PTSD and a loss of tissue in several regions of the brain. The team did not find any correlation between methylated SKA2 and depression.

“If you think about how PTSD relates to suicide, emerging evidence suggests that anxiety and stress, and the biochemical correlates of that stress, take a toll on the brain, especially in areas of the prefrontal cortex that regulate emotion and would normally inhibit self-destructive impulses,” says Miller. “Identifying the genes involved may give us new insights into the biological mechanisms linking PTSD to suicide.”

Even if other studies continue to correlate SKA2 with PTSD and brain cell death, this biomarker is unlikely to become a stand-alone indicator of suicide risk, Sadeh says. Whether or not a person is at risk for suicide depends not just on genetics, but on family history, social supports, mental illness, access to firearms, and myriad other factors. But she thinks this biomarker could provide a useful tool in conjunction with other tests.

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“It might help us improve risk prediction,” she says. “And if you have limited resources, it would help us direct them to those people who are at the highest risk.”

The possibility of genetic tests for PTSD or suicide risk raises questions, as well: could the tests someday prevent soldiers from entering combat, or screen people out of the military altogether? Miller says a genetic screen is unlikely in the foreseeable future, given the complex nature of PTSD and suicide risk. But he hopes that understanding genes like SKA2 will lead to better treatments. “The psychiatric medications we have for PTSD are still in early stages of development and only modestly effective,” he says. “If SKA2 expression turns out to be really important for brain health, we could try to develop drugs that enhance its activity or act on methylation at a particular brain site or use genetic profiles to match treatments to patients—that’s the exciting potential.”

Miller also hopes that the research may eventually apply to other groups known to suffer from PTSD and higher risk of suicide, such as victims of child abuse and sexual assault. “We’re still a ways from knowing whether studies in veterans apply to other at-risk populations,” he says, “but PTSD is not unique to veterans, nor is suicide.”

A version of this article was originally published in BU Research.