SKA2 suicide gene, genetic basis for suicide

SKA2 (spindle and kinetochore associated complex subunit 2) is a human gene.[1] Its protein product associates with the kinetochore in a protein complex with SKA1, and assists mitosis.[2] Genetic variants of SKA2 and epigenetic modifications of SKA2 have been linked to suicidal thoughts and behaviour in one study.[3][4]

Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors
Jerry Guintivano, Ph.D., Tori BrownAlison Newcomer, M.Sc., Marcus JonesOlivia Cox, B.Sc., Brion S. Maher, Ph.D., William W. Eaton, Ph.D., Jennifer L. Payne, M.D., Holly C. Wilcox, Ph.D., Zachary A. Kaminsky, Ph.D.
Received: January 02, 2014
Accepted: May 19, 2014
http://dx.doi.org/10.1176/appi.ajp.2014.14010008

Abstract
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Abstract

Considerable research suggests that suicide involves effects of genes, the environment, and their interaction. Analysis of three independent data sets of post-mortem brains revealed signs of increased methylation in one particular gene, SKA2, a finding that was extended to peripheral blood samples from other cohorts of prospectively followed individuals.
Objective:

Reliable identification of individuals at high risk for suicide is a priority for suicide prevention. This study was conducted to identify genes exhibiting epigenetic variation associated with suicide and suicidal behaviors.
Method:

Genome-wide DNA methylation profiling was employed separately on neuronal and glial nuclei in a discovery set of postmortem brains from the National Institute of Child Health and Human Development to identify associations with suicide. Pyrosequencing-based validation was conducted in prefrontal cortical tissue in cohorts from the Stanley Medical Research Institute and Harvard Brain Bank at McLean Hospital and peripheral blood from three living groups. Functional associations with gene expression, stress and anxiety, and salivary cortisol were assessed.
Results:

The DNA methylation scan identified an additive epigenetic and genetic association with suicide at rs7208505 within the 3′ untranslated region of the SKA2 gene independently in the three brain cohorts. This finding was replicated with suicidal ideation in blood from three live cohorts. SKA2 gene expression was significantly lower in suicide decedents and was associated with genetic and epigenetic variation of rs7208505, possibly mediated by interaction with an intronic microRNA, miR-301a. Analysis of salivary cortisol measurements suggested that SKA2 epigenetic and genetic variation may modulate cortisol suppression, consistent with its implicated role in glucocorticoid receptor transactivation. SKA2 significantly interacted with anxiety and stress to explain about 80% of suicidal behavior and progression from suicidal ideation to suicide attempt.
Conclusions:

These findings implicate SKA2 as a novel genetic and epigenetic target involved in the etiology of suicide and suicidal behaviors.

A blood test for suicide? - 07/30/2014
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Johns Hopkins School of Medicine
Jul 30, 2014 - Within this common mutation, they then found in some subjects an epigenetic modification that altered the way the SKA2 gene functioned ...

The blood test that could help prevent SUICIDE | Daily Mail ...
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Daily Mail
Jul 30, 2014 - Johns Hopkins scientists say stress produces a chemical alteration to a gene called SKA2 - and people with suicidal tendencies have lower ...

A blood test for suicide?
Alterations to a single gene could predict risk of suicide attempt
Release Date: July 30, 2014

Johns Hopkins researchers say they have discovered a chemical alteration in a single human gene linked to stress reactions that, if confirmed in larger studies, could give doctors a simple blood test to reliably predict a person’s risk of attempting suicide.

The discovery, described online in The American Journal of Psychiatry, suggests that changes in a gene involved in the function of the brain’s response to stress hormones plays a significant role in turning what might otherwise be an unremarkable reaction to the strain of everyday life into suicidal thoughts and behaviors.

“Suicide is a major preventable public health problem, but we have been stymied in our prevention efforts because we have no consistent way to predict those who are at increased risk of killing themselves,” says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “With a test like ours, we may be able to stem suicide rates by identifying those people and intervening early enough to head off a catastrophe.”

For his series of experiments, Kaminsky and his colleagues focused on a genetic mutation in a gene known as SKA2. By looking at brain samples from mentally ill and healthy people, the researchers found that in samples from people who had died by suicide, levels of SKA2 were significantly reduced.

Within this common mutation, they then found in some subjects an epigenetic modification that altered the way the SKA2 gene functioned without changing the gene’s underlying DNA sequence. The modification added chemicals called methyl groups to the gene. Higher levels of methylation were then found in the same study subjects who had killed themselves. The higher levels of methylation among suicide decedents were then replicated in two independent brain cohorts.

In another part of the study, the researchers tested three different sets of blood samples, the largest one involving 325 participants in the Johns Hopkins Center for Prevention Research Study found similar methylation increases at SKA2 in individuals with suicidal thoughts or attempts. They then designed a model analysis that predicted which of the participants were experiencing suicidal thoughts or had attempted suicide with 80 percent certainty. Those with more severe risk of suicide were predicted with 90 percent accuracy. In the youngest data set, they were able to identify with 96 percent accuracy whether or not a participant had attempted suicide, based on blood test results.

The SKA2 gene is expressed in the prefrontal cortex of the brain, which is involved in inhibiting negative thoughts and controlling impulsive behavior. SKA2 is specifically responsible for chaperoning stress hormone receptors into cells’ nuclei so they can do their job. If there isn’t enough SKA2, or it is altered in some way, the stress hormone receptor is unable to suppress the release of cortisol throughout the brain. Previous research has shown that such cortisol release is abnormal in people who attempt or die by suicide.

Kaminsky says a test based on these findings might best be used to predict future suicide attempts in those who are ill, to restrict lethal means or methods among those a risk, or to make decisions regarding the intensity of intervention approaches.

He says that it might make sense for use in the military to test whether members have the gene mutation that makes them more vulnerable. Those at risk could be more closely monitored when they returned home after deployment. A test could also be useful in a psychiatric emergency room, he says, as part of a suicide risk assessment when doctors try to assess level of suicide risk.

The test could be used in all sorts of safety assessment decisions like the need for hospitalization and closeness of monitoring. Kaminsky says another possible use that needs more study could be to inform treatment decisions, such as whether or not to give certain medications that have been linked with suicidal thoughts.

“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,” Kaminsky says. “We need to study this in a larger sample but we believe that we might be able to monitor the blood to identify those at risk of suicide.”

Along with Kaminsky, other Johns Hopkins researchers involved in the study include Jerry Guintivano; Tori Brown; Alison Newcomer, M.Sc.; Marcus Jones; Olivia Cox; Brion Maher, Ph.D.; William Eaton, Ph.D.; Jennifer Payne, M.D.; and Holly Wilcox, Ph.D.

The research was supported in part by the National Institutes of Health’s National Institute of Mental Health (1R21MH094771-01), the Center for Mental Health Initiatives, The James Wah Award for Mood Disorders, and The Solomon R. and Rebecca D. Baker Foundation.