Potential Biomarker for Suicide Vulnerability Identified

Only a fraction of people who experience powerful emotional events such as trauma, depression, or extreme stress have thoughts of suicide, and fewer still end up going through with it. Scientists have long been trying to find biological traits that may explain what makes some people more prone than others to think about or carry out suicide.

A gene known as SKA2 may hold some answers. Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, and colleagues analyzed the brain tissue of several people who had died by suicide and found higher than average levels of methylation around SKA2 compared with people who died by other means. Methylation is a chemical modification to a gene—an epigenetic change—that turns down that gene’s expression; so the more methyl groups on the SKA2 gene, the less SKA2 protein gets made.

There has been growing evidence that epigenetic patterns associated with suicide are different from those associated with other types of deaths (Psychiatric News, May 3, 2013), but cause and effect cannot be teased out postmortem. However, in this study, which appeared online in AJP in Advance July 30, the research group also identified heightened SKA2 methylation in blood samples of living people who were considered at risk for suicidal behaviors due to diagnoses of major depression or bipolar disorder.

“Individually, each of the groups we analyzed was pretty small, and every one had its own caveats,” said Kaminsky. “But as the same results kept rolling in across six different cohorts and two types of tissues, we thought there really is something going on here. And we saw evidence of elevated methylation prior to suicidal ideation, suggesting these changes are not an artifact that appears after suicidal behaviors start manifesting.”

SKA2 makes a protein known as a chaperone; it grabs on to glucocorticoid receptors inside a cell and escorts them to the nucleus, which helps regulate a cell’s response to the stress hormone cortisol. Inhibiting SKA2 via methylation could reduce this careful regulation and amplify the effects of a stressful or traumatic event.

Finding elevated SKA2 methylation in blood samples also suggests that this altered cortisol response is a systemic phenomenon—suicidal thoughts are not just in a person’s head. On a more practical note, detectable methylation changes in the blood lead to the potential of developing a simple blood test that might help measure suicide risk.

Kaminsky’s group assessed this possibility using the blood samples. They found that, by itself, SKA2 methylation was not predictive of any future suicidal thoughts or actions. However, when the researchers developed a model combining SKA2 methylation and anxiety status, they could predict suicidal behavior with about 80 percent accuracy.

“This is an intriguing study that identified a very meaningful gene,” said Eric Caine, M.D., the John Romano Professor of Psychiatry at the University of Rochester Medical Center. “However, before we get ahead of ourselves, we need to test this methodology and see if it applies in a larger, more general population.”

Kaminsky also acknowledges the need for replication of results, and to that end is collaborating with the U.S. Army STARRS (Study To Assess Risk and Resilience in Servicemembers) project to get such data.

“One of the biggest challenges in conducting suicide research is getting prospective samples,” he said. “STARRS offers a large repository of blood taken both pre- and post-deployment, which can offer a wealth of information to help us more accurately identify at-risk people.”

Kaminsky also hopes to better understand how the excess methylation develops. This current study did find that some of the subjects analyzed also had a variant sequence in the SKA2 gene region that might favor methylation, but while some genetic-epigenetic connection may exist, Kaminsky noted that the methylation changes were far more consistent among people who had thought about or completed suicide. “Epigenetics is the driving force,” he said.

This study was supported by the National Institute of Mental Health, National Institute on Drug Abuse, Johns Hopkins Center for Mental Health Initiatives, and others. ■

An abstract of “Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors” can be accessed here.