Introduction: The Multifaceted Nature of Suicidal Behavior
Suicide remains one of the most significant and complex challenges in global public health. While decades of research have established that suicidal behavior is heritable, identifying the specific genetic markers and understanding how they interact with an individual’s clinical phenotype and life history has proven difficult. Unlike many psychiatric disorders, suicidal behavior is not a single diagnosis but a complex phenomenon influenced by a constellation of internal traits, clinical conditions, and external environmental stressors.
In recent years, the development of polygenic scores (PGS) has offered a new lens through which to view these risks. A PGS aggregates the effects of thousands of genetic variants across the genome to provide a single measure of an individual’s genetic liability for a specific trait or behavior. In a landmark study published in JAMA Network Open, Kim et al. (2026) investigated how polygenic scores for suicide attempts (suicide-PGS) correlate with clinical characteristics, personality traits, and external stressors in both fatal and nonfatal suicidal behavior. This research provides a crucial step toward understanding the translational potential of genetic risk assessment in psychiatric settings.
Study Overview: Dissecting the Genetic and Environmental Architecture
The study utilized a case-control design to examine the interplay among suicide-PGS, clinical characteristics, and external stressors. The researchers aimed to determine if genetic liability for suicide attempt manifests through specific internal traits—such as hostility, impulsivity, or aggression—or if it is primarily mediated by the severity of clinical illness, such as depression.
Design and Methodology
The study included 1,699 individuals across two distinct cohorts. The first was a live cohort of 1,275 participants, including 239 who had attempted suicide and 1,036 control participants with no history of suicidal behavior. The second was a postmortem cohort of 424 individuals, consisting of 294 who died by suicide and 130 control individuals who died of other causes. Data collection occurred across three major urban centers: New York, Montreal, and Munich, spanning two decades of clinical observation (1991–2011).
The researchers employed genome-wide genotyping to calculate suicide-PGS. They then used sophisticated statistical models, including logistic and linear regressions, to assess associations between these scores and a variety of exposures, including:
1. Internal traits: Hostility, impulsivity, and aggression.
2. Clinical variables: Depression severity, suicidal ideation, and the frequency and lethality of previous attempts.
3. External stressors: Childhood abuse and recent stressful life events.
Key Findings: Validating Suicide-PGS and Identifying Trait Associations
The results of the study underscore the significant role of genetic liability in suicidal behavior, while also highlighting the specific pathways through which this risk may be expressed.
Genetic Liability in Fatal vs. Nonfatal Behavior
A primary finding of the study was the consistent association between suicide-PGS and suicidal behavior across both cohorts. In the live cohort, individuals with a higher suicide-PGS had an increased risk of having attempted suicide (odds ratio [OR], 1.35; 95% CI, 1.17-1.56). This association was remarkably similar in the postmortem cohort, where higher suicide-PGS was associated with death by suicide (OR, 1.34; 95% CI, 1.07-1.70). These findings suggest that the genetic architecture of nonfatal suicide attempts and fatal suicide overlaps significantly, reinforcing the validity of the suicide-attempt PGS as a marker for the broader spectrum of suicidal behavior.
The Role of Internal Traits: Aggression vs. Impulsivity
One of the most clinically relevant aspects of this study is the exploration of which personality traits correlate with genetic risk. Among participants who had attempted suicide, a higher suicide-PGS was significantly associated with lifetime aggression severity (b = 0.67; 95% CI, 0.41-0.94). Interestingly, the study found a negative association with hostility (b = -0.51; 95% CI, -0.82 to -0.19), suggesting that genetic risk for suicide may be more closely linked to outward or physical aggression rather than general hostileness.
Contrary to some previous hypotheses, suicide-PGS was not associated with impulsivity. This suggests that while impulsivity is a known risk factor for suicide, its contribution may be more environmentally driven or influenced by different genetic pathways than those captured by current suicide-attempt polygenic scores. Furthermore, the lethality of suicide attempts did not show a significant association with the PGS, indicating that the genetic drive toward the act of suicide may be distinct from the factors determining the method’s lethality.
Clinical Severity and History
Genetic liability was also reflected in the clinical course of psychiatric illness. Higher suicide-PGS was associated with greater depression severity (b = 0.20; 95% CI, 0.12-0.28) and a higher number of depressive episodes (b [SE], 0.11 [0.04]). This reinforces the idea that genetic risk for suicide is partly expressed through the severity and recurrence of underlying mood disorders.
The Interplay of External Stressors and Polygenic Risk
A critical question in psychiatric genetics is whether genetic risk makes individuals more vulnerable to environmental trauma or if genetics and environment act as independent risk factors. This study found that suicide-PGS was associated with reported childhood abuse (OR, 1.16; 95% CI, 1.02-1.33) and recent life stress (b [SE], 0.17 [0.05]).
However, the researchers noted that these stressors did not moderate the genetic associations with suicide. In other words, the genetic risk and the environmental risk factors appeared to be additive rather than interactive in this specific sample. This suggests that individuals with high genetic liability are more likely to have experienced childhood trauma—potentially due to genetic correlations between parental traits and the environment they provide—but the trauma itself did not significantly amplify the already present genetic risk for suicide.
Expert Commentary: Clinical Implications and Future Directions
This study provides a more nuanced understanding of the ‘suicidal diathesis’—the predisposition that makes some individuals more likely to act on suicidal thoughts during times of crisis.
Biological Plausibility and Trait Aggression
The strong link between suicide-PGS and aggression is particularly noteworthy. From a mechanistic standpoint, this supports the theory that certain biological pathways involving serotonergic or dopaminergic systems—which regulate both aggression and mood—may be central to the genetic risk of suicide. Clinicians might find this useful in risk assessment; patients with high levels of lifetime aggression may represent a subgroup with a higher genetic predisposition for suicidal acts, requiring more intensive monitoring and specific therapeutic interventions targeting emotional regulation.
The Limitation of Genetic Prediction
While the odds ratios (1.34–1.35) are statistically significant and scientifically important, they are not yet large enough to be used as standalone diagnostic or predictive tools in a clinical setting. Polygenic scores currently provide a population-level understanding of risk rather than an individual-level prediction. The study authors rightly emphasize that larger studies with even more detailed phenotyping are needed to refine these scores.
Furthermore, the lack of association with impulsivity and attempt lethality suggests that our current genetic models of suicide do not capture all facets of the behavior. Future research may need to integrate PGS for other traits, such as pain tolerance or executive function, to create a more comprehensive risk profile.
Conclusion: Moving Toward Integrated Risk Assessment
The study by Kim et al. highlights the incredible complexity of suicidal behavior. By demonstrating that genetic liability for suicide attempt is linked to specific traits like aggression and clinical markers like depression severity, it moves the field closer to a biological framework for suicide risk.
The findings underscore the importance of a holistic clinical approach. Knowing a patient’s history of childhood trauma and their levels of trait aggression can provide vital context to their genetic risk. As the field of genomic medicine continues to evolve, the integration of polygenic scores with traditional clinical assessments may eventually lead to more personalized and effective prevention strategies for those most at risk of self-harm.
References
1. Kim MJ, Galfalvy H, Singh T, Mann JJ. Polygenic Risk, Trait Variables, and External Stressors in Fatal and Nonfatal Suicidal Behavior. JAMA Netw Open. 2026;9(1):e2554325. doi:10.1001/jamanetworkopen.2025.54325.
2. Turecki G, Brent DA. Suicide and suicidal behaviour. Lancet. 2016;387(10024):1227-1239.
3. Mullins N, et al. Genome-wide association study of suicide attempt in the Psychiatric Genomics Consortium. Biol Psychiatry. 2022;91(3):313-327.
