When There Are No Signs: The Genetics Of Unwarning Suicide Deaths

This study analyzed nearly three thousand suicide deaths in Utah and showed that people who died by suicide without a history of suicidal ideation have significantly lower genetic predispositions to various psychiatric conditions, such as depression, anxiety, neuroticism, and PTSD, when compared to those with a history of ideation. Furthermore, individuals without ideation do not differ genetically from the general population in important aspects. These results indicate that half of suicide deaths follow a trajectory distinct from that traditionally associated with psychopathology, suggesting the existence of different risk mechanisms and opening new possibilities for prevention and research.

Suicide is a serious public health problem worldwide. In the United States alone, in 2022, nearly fifty thousand people died this way, and globally the deaths reach more than 700,000 per year. Although much is discussed about risk factors, it is still surprising how much remains unknown about who is truly at greater risk of dying by suicide.

The best known indicator is a previous attempt, but even this marker is limited, since only a small percentage of people who attempt suicide, between two and seven percent, end up dying from it.

Furthermore, half of the people who die by suicide never showed recorded signs of suicidal thoughts, and the other half had no psychiatric diagnosis. This shows that, although important, previous attempts and mental disorders do not fully explain the risk of death by suicide.

It was in this context that the current study was developed, using data from the Utah Suicide Mortality Research Study (USMRS), one of the most detailed and comprehensive databases on suicide deaths. Previous research from this database had already shown something intriguing: people who died by suicide without a history of suicidal ideation had significantly fewer recorded psychiatric diagnoses than people who died by suicide but had previously experienced suicidal thoughts.

This pattern could have two explanations. Perhaps these people simply never sought mental health care, meaning their problems were not recorded, or perhaps there was, in fact, an underlying genetic difference that placed them on distinct risk trajectories.

To investigate this possibility, the researchers used a method called polygenic scoring (PGS). In simple terms, this score works as a sum of thousands of small genetic influences that, together, increase or decrease someone's risk of developing a particular condition, such as depression, anxiety, or post-traumatic stress disorder.

Each gene contributes very little in isolation, but when all these contributions are added together, it is possible to estimate a general predisposition. The aim of the study was to compare the polygenic scores of two groups: people who died by suicide and had a history of suicidal ideation, and people who died by suicide but had never shown or recorded any suicidal thoughts before death.

The methodological aspect is especially important for understanding the robustness of these findings. The researchers selected genetic statistics from twelve large international studies on different neuropsychiatric conditions.

These studies were chosen because they had enormous samples, because they included populations with ancestry similar to the Utah population, and because they were recent and rigorous studies. Using this data, they calculated the polygenic scores of each deceased individual from genetic material already available in the database.

After that, the researchers divided the cases into two groups: the SD-S group, composed of people who demonstrated suicidal ideation at some point, and the SD-N group, formed by people with no record of suicidal ideation.

Each person's polygenic score was then compared between the two groups, always taking into account important factors that could distort the results, such as age, sex, and genetic ancestry. This is essential because differences between groups could be attributed not to genetic risk, but to demographic or population differences.

The scores were also compared with a large control sample of nearly 20,000 people from the general population. The study also investigated whether the patterns repeated themselves when people were divided between those who died before the age of fifty and those who died after that age, to see if the relationship between genetics and suicidal behavior changed over the course of life.

The results showed that people who died by suicide without a history of suicidal ideation had significantly lower genetic scores for several psychiatric conditions, especially major depression, anxiety, neuroticism, and post-traumatic stress disorder.

They also had lower scores for genetic risk of Alzheimer's disease, which was included in the study because some neurodegenerative conditions can influence emotional and behavioral functioning. In other words, genetically, these people resembled typical profiles of psychiatric vulnerability less and the general population more.

Importantly, when compared to the control group, the group without suicidal ideation did not differ statistically from the general population in scores for depression, neuroticism, and Alzheimer's disease, reinforcing the idea that they did not have elevated genetic predispositions to psychiatric conditions.

These patterns suggest that there are, in fact, two different trajectories that can lead to death by suicide. The first is the best-known one, related to mental disorders, persistent emotional suffering, suicidal ideation, and psychiatric treatments.

The second seems to involve people who do not have a strong genetic predisposition to psychiatric disorders, who may not manifest clear symptoms or seek help, and who may be influenced by very acute situational factors, impulsivity, extreme stress, or unexpected contexts. This implies that, for a considerable portion of suicide deaths, the classic signs do not appear, neither in behavior nor in genetics.

The conclusions are important for rethinking prevention and research strategies. Traditionally, mental disorders are believed to be the central core of suicide risk, but the findings show that this does not apply to all cases.

It is necessary to develop new ways to identify risk in people who do not present traditional symptoms. The study also reinforces the importance of analyzing suicide not as a unitary phenomenon, but as a set of distinct pathways, requiring different prevention approaches.

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Genetic Liabilities to Neuropsychiatric Conditions in Suicide Deaths With No Prior Suicidality

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

JAMA Network Open. 2025;8;(10):e2538204.

DOI: 10.1001/jamanetworkopen.2025.38204

Abstract:

Although suicide attempt is the most robust estimator of suicide death, few individuals who attempt it go on to die by suicide (<10%), and approximately 50% of suicide deaths occur in the absence of evidence of prior attempts. The risks are particularly poorly understood in this group. To study underlying polygenic liabilities among suicide deaths without evidence of prior nonfatal suicidality (SD-N) compared with suicide deaths with prior suicidality (SD-S), testing prior results showing significantly lower clinical risks of neuropsychiatric traits in SD-N vs SD-S. In this cohort study, polygenic scores (PGS) were computed using summary statistics from 12 published source studies, then compared across SD-N and SD-S groups taken from the Utah Suicide Mortality Research Study (cases accrued between December 1998 and October 2022). PGS from the suicide death cohorts were also compared to unselected population controls. Evidence of prior suicidality was determined from diagnoses and clinical notes. Cohort differences in PGS reflecting neuropsychiatric conditions were tested using analysis of covariance, adjusting for sex, age, and genetic ancestry, followed by additional analyses within sex and within subgroups defined by age at death (50 years or younger vs older than 50 years). PGS spanned 12 neuropsychiatric conditions. Data were analyzed between July 2024 and July 2025. The SD-N cohort (n = 1337) had significantly more male suicide deaths (1105 [82.65%] vs 974 [67.95%]), with an older mean (SD) age at death (47.5 [18.9] vs 41.4 [15.6] years) than the SD-S cohort (n = 1432). The control cohort (n = 19 499) had significantly fewer males (8597 [44.09%]) than both suicide death subsets. Genetic ancestry was similar across the SD-N and SD-S groups (96.77% and 96.81% European ancestry), and control (97.38% European ancestry) groups. Socioeconomic status was not significantly different across suicide cohorts adjusted for age and sex (occupation ranking SD-N mean [SD], 57.16 [24.54]; SD-S mean [SD], 54.72 [25.29]; t = 1.30; P = .70; maximum education SD-N mean [SD], 2.70 [1.12]; SD-S mean [SD], 2.67 [1.13]; Fisher exact test P = .38). Comparing SD-N to SD-S revealed significantly lower (false discovery rate P < .05) PGS in the SD-N group for major depressive disorder (adjusted mean difference, 0.085 [95% CI, 0.018-0.152]; P = .01), depressed affect (adjusted mean difference, 0.081 [95% CI, 0.012-0.149]; P = .02), anxiety (adjusted mean difference, 0.091 [95% CI, 0.021-0.161]; P = .01), neuroticism (adjusted mean difference, 0.102 [95% CI, 0.033-0.171]; P = .004), and Alzheimer disease (adjusted mean difference, 0.090 [95% CI, 0.021-0.1658]; P = .01), and lower (false discovery rate P < .10) PGS in SD-N for posttraumatic stress disorder (adjusted mean difference, 0.070 [95% CI, 0.001-0.139]; P = .04). Of note, SD-N PGS were not significantly different from controls for depressed affect (adjusted mean difference, 0.037 [95% CI, −0.019 to 0.093]), neuroticism (adjusted mean difference, −0.001 [95% CI, −0.057 to 0.055]), or Alzheimer disease (adjusted mean difference, −0.027 [95% CI, −0.083 to 0.029]). In this cohort study, SD-N showed significantly different genetic liabilities to neuropsychiatric conditions from SD-S. Results have implications for future suicide research and prevention for persons at risk of mortality.