Recent research indicates that people who die by suicide without a prior history of suicidal behavior may possess a distinct biological profile compared to those with a known history of distress. A new study published in JAMA Network Open reveals that these individuals carry significantly fewer genetic risk factors for mental health conditions such as depression and anxiety. These findings suggest that suicide risk in this specific group may be driven by different mechanisms than researchers previously assumed.
Public health officials identify suicide as a severe and persistent crisis, with hundreds of thousands of lives lost globally each year. Medical professionals typically rely on a patient’s history of suicide attempts or expressed suicidal thoughts to gauge future risk. This history is currently the most reliable predictor available to clinicians.
However, this metric has substantial limitations. Statistics show that roughly half of all suicide deaths occur in individuals who have no documented record of suicidal thoughts or behaviors. These deaths often come as a shock to family members and medical providers alike.
A large portion of these unexpected deaths occurs in individuals who also lack a formal diagnosis of a mental health disorder. The prevailing assumption in the medical community has been that these individuals likely suffered from undiagnosed mental illnesses. Under this theory, they faced barriers to care or screening that prevented their conditions from being recognized.
Researchers at the University of Utah Huntsman Mental Health Institute sought to test this assumption. They hypothesized that if the lack of diagnosis was simply an administrative failure, the underlying genetic risk for mental illness should remain high in this group. Alternatively, they proposed that these individuals might differ biologically from those with established histories of suicidality.
The study utilized data from the Utah Suicide Mortality Research Study. This resource links medical examiner records with genetic information and electronic health records. The team examined data from over 2,700 individuals who died by suicide between 1998 and 2022.
The researchers divided these individuals into two distinct cohorts. The first group consisted of 1,432 individuals who had evidence of prior suicidality in their medical records or clinical notes. The second group included 1,337 individuals who died by suicide but had no such documented history.
To assess biological risk, the team calculated polygenic scores for each individual. A polygenic score is a statistical tool that aggregates the effects of thousands of small genetic variations. It does not provide a diagnosis but estimates an individual’s genetic liability or predisposition for a specific trait.
The team calculated these scores for twelve different neuropsychiatric conditions. These included major depressive disorder, anxiety, bipolar disorder, and schizophrenia. They also generated scores for traits such as neuroticism and for neurodegenerative conditions like Alzheimer’s disease.
For comparison, the researchers analyzed the same genetic markers in a control group of nearly 20,000 people from the general population. This allowed them to establish a baseline for what constitutes average genetic risk. They adjusted their analysis to account for variables such as age, sex, and genetic ancestry.
The analysis revealed significant genetic differences between the two suicide cohorts. The group without prior suicidal history had much lower polygenic scores for major depressive disorder and anxiety than the group with a known history. Their genetic liability for neuroticism and posttraumatic stress disorder was also significantly lower.
When compared to the general population control group, the findings were even more specific. The genetic scores for depressed affect and neuroticism in the group without prior suicidality were statistically indistinguishable from the controls. This indicates that their genetic baseline for these mood-related traits was effectively average.
The study also identified traits that shared genetic liability across both suicide groups. Polygenic scores for schizophrenia were elevated in both cohorts compared to the general population. This was true even though the group without prior suicidality rarely had clinical diagnoses of schizophrenia.
Similarly, genetic risks for attention-deficit/hyperactivity disorder and alcohol use were elevated in both groups relative to controls. This suggests that traits related to impulse control may be a common factor in suicide mortality. This commonality appears to exist regardless of whether an individual has a history of suicidal behavior.
The researchers performed additional analyses to see if these patterns held true across different demographic subgroups. They found that the results varied somewhat depending on the sex of the individual and their age at death.
Among women who died without prior warning signs, genetic scores for autism were significantly higher than in the general population. This specific elevation in autism risk was not observed in the male subjects within the same group. This finding points to potential sex-specific pathways that warrant further investigation.
Age also played a role in the genetic profiles. For individuals over the age of 50 in the group without prior history, genetic scores for anxiety and Alzheimer’s disease were notably lower than in the group with prior history. In younger individuals, the differences were more pronounced regarding depression and neuroticism.
These results challenge the idea that increased screening for depression will identify all individuals at risk for suicide. “A tenet in suicide prevention has been that we just need to screen people better for associated conditions like depression,” said Hilary Coon, a professor of psychiatry at the University of Utah and the study’s lead author. “But for those who actually have different underlying vulnerabilities, then increasing that screening might not help for them.”
The study suggests that a focus solely on diagnosing mental illness may miss a substantial portion of the at-risk population. If an individual does not possess the genetic vulnerability for depression, they may never develop the symptoms that current screening tools are designed to catch.
Coon emphasized the need to broaden the scope of suicide research. “That is important in widening our view of who may be at risk,” she said. “We need to start to think about aspects leading to risk in different ways.”
The authors acknowledge several limitations to their work. The study participants were primarily of European ancestry, which means the findings may not apply equally to other genetic populations. The researchers relied on medical records to determine prior suicidality, and it is possible that some individuals had undocumented histories of distress.
Additionally, while the polygenic scores provide a measure of biological risk, they do not determine destiny. Environmental factors and life experiences play a massive role in suicide risk. The current study did not account for social or environmental exposures that might interact with these genetic profiles.
Future research will need to investigate non-psychiatric factors that might contribute to mortality in this group. Researchers are interested in exploring the roles of physical health conditions, chronic pain, and inflammation. Understanding how these factors intersect with genetic liability could lead to more targeted prevention strategies.
The study provides a foundation for categorizing suicide risk into more precise subtypes. By recognizing that not all suicide deaths stem from the same biological origins, medical professionals may eventually develop better tools to identify those who currently fly under the radar.
The study, “Genetic Liabilities to Neuropsychiatric Conditions in Suicide Deaths With No Prior Suicidality,” was authored by Hilary Coon, Andrey A. Shabalin, Eric T. Monson, Emily DiBlasi, Seonggyun Han, Lisa M. Baird, Erin A. Kaufman, Douglas Tharp, Michael J. Staley, Zhe Yu, Qingqin S. Li, Sarah M. Colbert, Amanda V. Bakian, Anna R. Docherty, Andrew M. McIntosh, Heather C. Whalley, Dierdre Amaro, David K. Crockett, Niamh Mullins, and Brooks R. Keeshin.
