Can Specific Genes in the Blood Help Predict Suicide Risk?

BACKGROUND:

A major aim in the field of suicide prevention research is to amplify our ability to detect factors in individuals that indicate a potentially elevated level of risk – ideally before suicidal thoughts and behaviors enter the picture. Many biological researchers are working to do this by uncovering biomarkers (measurable substances that can indicate the presence of a disease or condition) that may be associated with suicide risk and the mental health conditions most associated with it.

Biomarkers can take many forms, including chemical compounds, genetic sequences, and even behavioral patterns. In the case of suicide prevention research, some scientists have focused on finding genetic differences that are specifically active for people who die by suicide. But this search is complicated by both the biological and methodological realities of conducting genetic research.

So far, many potential biomarkers have been identified in the brain by studying tissue samples from human donors after their death. While these findings have been helpful in mapping out the biological mechanisms that could contribute to suicide risk, in order to serve the goal of risk detection and intervention (we can’t study brain samples in living people), we need to be able to match these biomarkers in other areas of the body, such as the blood.

One possible tool that having a suicide biomarker in the blood could add to the suicide prevention toolkit (along with therapeutic and safety planning approaches) is the ability to create a blood test to help healthcare professionals identify individuals at risk for suicide, monitor them closely, and intervene earlier with more targeted treatment if needed.

Further complicating this search though, is a protective membrane surrounding the brain called the blood-brain barrier. This membrane plays an essential role in maintaining the delicate environment the brain needs in order to function by separating the blood vessels in the brain from the rest of the body. Much like a bouncer running the door at an exclusive nightclub (the brain is the nightclub in this case), the blood-brain barrier blocks potential pathogens and toxins from getting in and allows only select molecules and vital nutrients (VIPs) from the bloodstream through the door and into Club Central Nervous System.

Though this barrier in the brain is vital to neurological functioning – and ultimately our survival – it has also been a barrier to researchers because it limits how clear of a picture we can paint of what’s going on inside the brain from outside the wall of its protection. Just because a biomarker is in the brain doesn’t mean it's present in the rest of the body, and so researchers have been left to figure out a way to build a bridge over the barrier – from the brain and to the arm.

With this in mind, Dr. Adolfo Sequeira set out to test a new method of analyzing matched brain and blood samples to see if differences in gene expression (biomarkers) existed in both the brain and the blood between individuals who died by suicide and those who died of other causes.

QUESTION:

Can we identify specific genes in the blood that indicate suicide risk for individuals with Major Depressive Disorder?

STUDY:

Dr. Sequeira obtained and compared the blood and brain samples of 45 deceased individuals from the Pritzker Brain Bank at the University of California, Irvine. The majority of the samples came from individuals with Major Depressive Disorder (MDD), as this is the most common psychiatric diagnosis in suicide. He divided the samples into three groups:

• (MDD-S) – Individuals with Major Depressive Disorder who died by suicide
• (MDD-NS) – Individuals with Major Depressive Disorder who died by other means
• Non-Psychiatric controls

A targeted gene expression approach was developed for this study in which RNA (genetic information) was extracted from the provided brain and blood samples and analyzed using a new and unique platform called, NanoString nCounter Analysis System, which quantifies and profiles genetic expression. The NanoString platform is also less sensitive to molecular degradation (RNA naturally breaks down over time and can render unreliable data as a result).

Dr. Sequeira and his colleagues then analyzed and compared the data to see if there were significant differences in genetic expression between the groups, especially between the MDD-S and MDD-NS groups.

RESULTS:

Dr. Sequeira and his colleagues identified significant differences in the way genes were expressed between groups in brain samples, in blood samples, and, crucially, a few that were significantly differentiated in both brain and blood samples.

In just the blood samples, 14 genes showed differences between MDD-S and MDD-NS groups. While in the brain samples, 17 genes displayed significant differentiation. Most remarkably though, Dr. Sequeira found 4 genes that had significant differences between suicide and non-suicide deaths in both the blood and the brain (SOX9, PER3, CD19, TERF1).

These 4 specific genes are involved in stress response changes, immune dysregulation, circadian rhythm dysfunction, and cellular maintenance. While these potential blood biomarkers may be associated with suicide risk, it's important to note that they may not be directly causing the suicidal behavior.

This is the first study to uncover suicide specific gene expression changes both in blood and brain tissue from the same MDD subjects to develop a biomarker in blood that could predict individuals at highest risk for suicide. More research is needed to validate these findings and confirm the utility of the discovered blood biomarkers, but the work and methods of Dr. Sequeira and his colleagues are a big step towards improving our ability to detect biological factors in individuals that indicate an elevated level of risk.

TAKEAWAYS:

• In the field of suicide prevention research, biological scientists are focused on finding biomarkers that indicate elevated risk for suicide.
• Researchers are developing ways to bypass the challenges the blood-brain barrier presents in mapping out the molecular makeup in the brain.
• There is potentially a suicide specific genetic signature in patients with MDD that could prove useful in suicide risk detection and help healthcare providers save lives.
• More research is needed to validate these findings and put these biomarkers to use.

Adolfo Sequeira, Ph.D.

Grant Type: 2019 Standard Research Grant – $100,000

Grant Page: Comparison of Brain and Blood Suicide Signatures: From Mechanisms to Biomarkers

Grant Related Publication:

1. Mamdani, F., Weber, M.D., Bunney, B. et al. Identification of potential blood biomarkers associated with suicide in major depressive disorder. Transl Psychiatry 12, 159 (2022). https://doi.org/10.1038/s41398-022-01918-w