Many who die by suicide aren’t depressed, genetic research suggests
image:
Hilary Coon, PhD, lead author on the study.
view moreCredit: Charlie Ehlert / University of Utah Health
Among friends and family of those who die by suicide, a common refrain is: I didn’t know.
While some people who die by suicide have prior attempts, about half of people who die by suicide have no documented suicidal thoughts or behaviors, nor do they have known psychiatric conditions associated with suicide risk, like depression. They have no previous clear indicators that they might be at risk at all.
A new genetic study at University of Utah found that people in this group of unexpected suicides aren’t just flying under the clinical radar via lower access to psychiatric services—their underlying risk factors may be fundamentally different.
The research found that people who die by suicide without prior non-fatal suicidal thoughts or behaviors have fewer psychiatric diagnoses and also fewer underlying genetic risk factors for psychiatric conditions compared to people who had shown these warning signs before dying by suicide.
“There are a lot of people out there who may be at risk of suicide where it’s not just that you’ve missed that they’re depressed, it’s likely that they’re in fact actually not depressed,” says Hilary Coon, PhD, professor of psychiatry in the Spencer Fox Eccles School of Medicine at the University of Utah and first author on the study.
“That is important in widening our view of who may be at risk. We need to start to think about aspects leading to risk in different ways.”
The results, published in JAMA Network Open, upend conventional beliefs about suicide risk and suggest new approaches to help save lives.
Uncovering hidden risk
Other research had shown that people who die by suicide without prior known suicidality are less likely to have psychiatric diagnoses, such as depression, compared to people with documented suicidal thoughts or behaviors. But nobody knew the root cause of this difference. Maybe, researchers thought, people without known suicidality are still just as depressed or anxious—they’re just undiagnosed.
But Coon’s team was surprised to find that this isn’t the case. Instead, they found that this group has different genetic risk factors from people with known suicidality. By comprehensively analyzing anonymized genetic data from more than 2,700 people who died by suicide, the researchers found that people without prior suicidality tend to have fewer genetic risk factors for several psychiatric conditions, including major depressive disorder, anxiety, Alzheimer’s disease, and PTSD.
The genetic data also suggests that this group isn’t any more likely than the general population to have milder conditions, like depressed mood and neuroticism.
This means that conventional wisdom on how to reduce suicide may need to be rethought. “A tenet in suicide prevention has been that we just need to screen people better for associated conditions like depression,” Coon explains. “And if people had the same sort of underlying vulnerabilities, then additional efforts in screening might be very helpful. But for those who actually have different underlying vulnerabilities, then increasing that screening might not help for them.”
Helping those most at risk for suicide
Figuring out how to find and treat these “hidden” at-risk individuals is a major focus of Coon’s upcoming research. Previous studies with clinical data have shown potential links between suicide risk and hard-to-treat conditions like chronic pain. Coon is also investigating how other physical disorders, such as inflammation and respiratory conditions, may impact suicide risk. Her work will also focus on traits that may confer resilience to suicide.
Coon emphasizes that, on their own, individual genetic risk factors related to suicide have very small effects on risk, and there’s no single gene—or combination of genes—that causes suicide. Environmental and societal contexts are crucial contributors to risk, and understanding the interplay between the environment and underlying biology will be essential to discovering who’s at risk.
“We hope our work will begin to define subsets of individuals at risk, and also the contexts in which these risk characteristics may be important,” Coon says. “If people have a certain type of clinical diagnosis that makes them particularly vulnerable within particular environmental contexts, they still may not ever say they’re suicidal. We hope our work may help reveal traits and contexts associated with high risk so that doctors can deliver care more effectively and specifically. ” Better identification of at-risk individuals will help people get the care they need.
###
Do you need help? Call 988 to reach a free, confidential 24/7 support line for suicidal crisis or emotional distress. The Huntsman Mental Health Institute Crisis Care Center also offers 24/7 walk-in mental health services for adults. Additional information and assistance can be found through the Utah Chapter of the American Foundation for Suicide Prevention.
Are you concerned about a loved one or friend? Asking is the single most effective intervention for suicide. Learn how to help.
###
This research is published in JAMA Network Open as “Genetic Liabilities to Neuropsychiatric Conditions in Suicide Deaths With No Prior Suicidality.”
The work was supported by the National Institute of Mental Health (grants R01MH122412, R01MH123489, R01ES032028, and R01MH123619), Janssen Research & Development, the American Foundation for Suicide Prevention (grant BSG-1-005-18), the Brain & Behavior Research Foundation–National Alliance for Research on Schizophrenia and Depression (grants 28132, 28686, and 31249), and the Clark Tanner Foundation. Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Journal
JAMA Network Open
Method of Research
Observational study
Subject of Research
People
Article Title
Genetic Liabilities to Neuropsychiatric Conditions in Suicide Deaths With No Prior Suicidality
Probing new mechanisms of depression and anxiety
Mouse study reveals a molecular mechanism that may underlie depressive- and anxiety-like symptoms.
In a new JNeurosci paper, Tian-Ming Gao and colleagues, from Southern Medical University, explored how adenosine triphosphate (ATP) signaling relates to depression and anxiety using male mice. ATP is a molecule that not only provides energy but also supports communication between neurons. The researchers focused on ATP signaling in a brain region implicated in depression called the hippocampus.
Male mice that were more likely to acquire depressive- and anxiety-like symptoms following long-term stress had less ATP levels and reduced expression of a protein involved in ATP release (connexin 43). When the research team genetically dampened or deleted connexin 43 in cells that release ATP in another group of mice, this alone led to depressive- and anxiety-like behaviors and lowered ATP levels. Bridging the findings together, in distressed mice, restoring connexin 43 in the hippocampus brought ATP levels up to normal and improved behavioral outcomes.
Says Gao, “This is the first direct evidence that deficient ATP release in [a region of the] hippocampus drives both depressive- and anxiety-like behaviors, revealing a shared molecular pathway [for these conditions].” Gao also emphasizes that the findings linking connexin 43 to this mechanism point to a potential treatment target for treating depression and anxiety when they occur at the same time. Of note, the researchers plan to assess both sexes in future studies.
###
Please contact media@sfn.org for full-text PDF.
About JNeurosci
JNeurosci was launched in 1981 as a means to communicate the findings of the highest quality neuroscience research to the growing field. Today, the journal remains committed to publishing cutting-edge neuroscience that will have an immediate and lasting scientific impact, while responding to authors' changing publishing needs, representing breadth of the field and diversity in authorship.
About The Society for Neuroscience
The Society for Neuroscience is the world's largest organization of scientists and physicians devoted to understanding the brain and nervous system. The nonprofit organization, founded in 1969, now has nearly 35,000 members in more than 95 countries.
Journal
JNeurosci
Article Title
ATP Release Deficiency Through Astrocytic Connexin 43 in the Dorsal Hippocampus Promotes Depressive- and Anxiety-like Behaviors
Article Publication Date
24-Nov-2025
