Alterations in a gene linked to stress reactions may eventually help clinicians identify patients at increased risk for suicidal behavior, including attempts, potentially by way of a simple blood test, new research shows.
Investigators at the Johns Hopkins University School of Medicine in Baltimore, Maryland, examined postmortem brains and found a genetic and epigenetic link between suicide and the single- nucleotide polymorphism (SNP) rs7208505 "within the 3' untranslated region of the SKA2 gene."
The investigators were able to then replicate this finding in 2 other postmortem brain cohorts and in blood draws from 3 live participant cohorts. They found a significantly lower SKA2 gene expression in those with suicidal behavior and an association with variations of rs7208505.
A final analysis, this time of salivary cortisol, showed that SKA2 variations may modulate cortisol suppression.
"After each cohort analysis, we became more and more convinced that we actually found something real," principal investigator Zachary A. Kaminsky, PhD, assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and assistant professor of mental health at the Johns Hopkins Bloomberg School of Public Health, told Medscape Medical News.
Dr. Kaminsky noted that, if replicated in larger studies, the findings may eventually lead to a simple blood test that can be used in clinical practice.
"With a test like ours, we may be able to stem suicide rates by...intervening early enough to head off a catastrophe," he said in a release.
The study was published July 30 in the American Journal of Psychiatry.
Goal: Reduction in US Suicide Rate
The goal of the National Action Alliance for Suicide Prevention for the next 5 years is a 20% decrease in the United States' suicide rate, report the investigators.
However, "we have been stymied in our prevention because we have no consistent way to predict those who are at increased risk of killing themselves," said Dr. Kaminsky.
"We're interested in studying molecular marks as they relate to psychiatric phenotype and specifically an epigenetic mark or DNA methylation. That can be thought of as a molecular mark connected to genes that act as dimmers on light switches, because they can turn up or down the level of gene expression," he explained.
The researchers first sought to identify associations with suicide using postmortem prefrontal cortical tissue samples in 3 cohorts with a total of 168 individuals. Peripheral blood samples were also examined from live participants from 3 previous studies (n = 22, 51, and 325).
Finally, stress and anxiety and salivary cortisol levels were examined for functional associations.
Results from the brain sample analyses showed that individuals who had died by suicide had significantly lower levels of SKA2 than those who did not die by suicide.
The SKA2 gene is involved in the brain's response to stress hormones. Alterations in or lower levels of the gene can keep the stress hormone receptor from suppressing the release of cortisol.
The samples from suicide decedents also had higher levels of DNA methylation.
When examining participants in the 3 living cohorts, those who reported having suicidal thoughts or who had attempted suicide in the past had methylation increases at SKA2, "consistent with the brain findings," report the investigators.
In addition, waking cortisol level was significantly associated with suicidal ideation and with epigenetic variation at rs7208505 in the 22-person cohort study that examined this measurement.
"As SKA2 is implicated in glucocorticoid signaling, we reasoned that cortisol levels may interact with SKA2 to mediate suppression of future cortisol," explain the investigators.
There was also a significant interaction between stress and anxiety scores and rs7208505 genotype.
Finally, after creating a model based on the blood analysis and using anxiety status as the covariate, the investigators were able to predict which of the participants were experiencing suicidal thoughts with 80% accuracy. The percentage went up 90% for those with a more severe risk of attempting suicide.
"These findings implicate SKA2 as a novel genetic and epigenetic target involved in the etiology of suicide and suicidal behaviors," write the investigators.
Dr. Kaminsky added that a future blood test based on these findings might be especially helpful for the military.
He noted that military members found to have the gene mutation should perhaps be better monitored upon their return from deployment. The test might also be useful as part of a suicide risk assessment in psychiatric emergency departments.
"We have found a gene that we think could be really important for consistently identifying a range of behaviors from suicidal thoughts to attempts to completions," said Dr. Kaminsky, although he added that "it isn't yet ready for prime time" and that more studies are needed.
Predicting Risk Critical
"I think this is a really impressive and thoughtful study that looked at data at multiple levels," Aoife O'Donovan, PhD, assistant professor in the Department of Psychiatry at the University of California, San Francisco, told Medscape Medical News.
"It was interesting that across all of these different analyses, there were convergent findings suggesting that factors related to the SKA2 gene might be involved in suicidal ideation and behavior."
She was also impressed that the model had such a high accuracy rating in predicting risk. However, she noted that the prediction depended on the interaction with stress and anxiety.
"Once again, this paper, like so many others in psychiatry, highlights that we need to think about how the environment and the underlying biology interact with each other," she said.
Dr. O'Donovan, who was not involved with this research, published a study last year showing that adults with major depressive disorder and high suicidal ideation also have higher levels of inflammation, as shown through blood draws.
"It's clear that the genetic vulnerability for many mood disorders only become apparent when individuals are exposed to very stressful life experiences. Stress plays an important role in many psychiatric disorders, and when examining biomarkers, I think we need to bear that in mind," she said.
Dr. O'Donovan, who is also a research psychologist at the Veteran's Affairs Medical Center in San Francisco, agreed with Dr. Kaminsky that something needs to be done about the high suicide rate in veterans.
"Models that allow us to predict risk are going to be very important for the military. That's clearly a major priority for the future."
Seven of the study authors and Dr. O'Donovan have reported no relevant financial relationships. Dr. Kaminsky and 1 of the other study authors have reported being coinventors on a patent that uses genetic and epigenetic variation at the SKA2 locus to evaluate risk for suicidal behavior. The remaining study author reports having received legal consulting fees from Pfizer, AstraZeneca, and Johnson and Johnson; and research support from Corcept Therapeutics.
Am J Psychiatry. Published online July 30, 2014. Abstract
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Cite this: Suicide Blood Test? - Medscape - Aug 01, 2014.