Individuals Without Prior Suicidality Exhibit Fewer Genetic Risk Factors — Evidence Review

A major genetic study from the University of Utah finds that about half of people who die by suicide have no previous psychiatric diagnoses or warning signs, and show fewer genetic risk factors for common psychiatric disorders than those with known suicidality. While prior research has established genetic and biological contributions to suicide risk, this study suggests a distinct, "hidden" group not captured by conventional screening; related studies generally support a complex interplay between genetics, biology, and environment in suicidality.

• Many earlier studies have linked suicidal behavior to both familial (heritable) and specific genetic factors, but most genetic associations are modest and often tied to psychiatric conditions like depression, which the new study suggests are less relevant for this "hidden" group 1 2 3 4 5.
• Emerging evidence also implicates biological mechanisms beyond classic psychiatric genetics, such as neuroinflammation and immune system activity, in suicide risk; however, these biomarkers are weak predictors on their own and may not fully account for sudden, unanticipated suicides 7 9 10.
• Warning signs and risk factors for suicide are highly variable, and multiple studies highlight that a substantial proportion of suicides occur without clear warning behaviors or prior diagnoses, making prediction and prevention especially challenging for such cases 11 12 13 14.

Study Overview and Key Findings

While suicide prevention efforts often focus on identifying individuals with psychiatric disorders or a history of suicidal ideation, this study addresses a crucial gap: understanding suicide deaths that occur without any prior warning signs or recognized risk factors. Using comprehensive genetic data from over 2,700 individuals who died by suicide, the research aims to determine whether these "unexpected" cases are simply missed by screening, or if they represent a distinct biological and clinical subgroup. The findings have implications for how suicide risk is conceptualized and may inform broader prevention strategies that go beyond traditional psychiatric screening.

Property	Value
Organization	University of Utah
Journal Name	JAMA Network Open
Authors	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, Brooks R. Keeshin
Population	Individuals who died by suicide without prior suicidality
Sample Size	more than 2,700 people
Outcome	Genetic risk factors for psychiatric conditions
Results	People without prior suicidality have fewer genetic risk factors.

Literature Review: Related Studies

To contextualize the new findings, we searched the Consensus research paper database (200M+ papers) using targeted queries to identify relevant literature. The following search queries were used:

1. suicide genetic risk factors
2. biological mechanisms of suicidality
3. warning signs in suicide prevention

Topic	Key Findings
How do genetic and biological factors contribute to suicide risk?	- Genetic associations with suicide risk are modest, often linked to serotonergic genes (e.g., TPH1, 5-HTTLPR), but findings are inconsistent and do not fully explain suicidality 1 5. - Biological correlates such as neuroinflammation, immune dysregulation, and altered neurochemistry are implicated, but their predictive power is generally weak and not specific to all suicide cases 6 7 9 10.
What is the relationship between psychiatric disorders and suicide risk?	- Suicide risk is elevated among individuals with psychiatric disorders, especially depression, but not all suicides occur in people with diagnosable psychiatric conditions 2 3 4 8. - Some genetic risk factors for suicide overlap with those for major depressive disorder, but there are also distinct genetic contributions separate from psychiatric diagnoses 3 4.
Are there reliable warning signs or predictors for suicide?	- Warning signs (e.g., mood changes, seeking lethal means) are useful for some suicides, but many cases show few or no clear warning signs, making prediction difficult, especially in certain methods or subgroups 11 12 13 14. - Some suicides occur without any new or noticeable behaviors, and warning signs may not always be present or recognized even in clinical populations 12 13 14.
What are the limitations of current biological and clinical risk assessments?	- Biological factors (e.g., cytokines, genetic polymorphisms) have limited predictive utility for suicide on their own, and most known markers have weak associations after accounting for confounders 5 9. - Risk assessment is complicated by the complex interplay of genetic, biological, psychological, and environmental factors, and many individuals at risk are not detected by current screening methods 8 9.

How do genetic and biological factors contribute to suicide risk?

Genetic research on suicide has identified several candidate genes and biological pathways, but results are often inconsistent and the effect sizes small. The new study's finding that people who die by suicide without prior warning signs have fewer genetic risk factors for common psychiatric disorders aligns with earlier literature emphasizing the complexity and modest impact of genetic contributions. Biological mechanisms such as neuroinflammation and stress response pathways are increasingly recognized, but their role in predicting suicide—especially in the absence of psychiatric illness—remains unclear.

• Genetic associations with suicide risk are often limited to serotonergic system genes (e.g., TPH1, 5-HTTLPR), but the overall picture is complex and not fully understood 1 5.
• Biological markers such as inflammatory cytokines and immune activation are associated with suicide risk, though their predictive capacity is weak 7 9 10.
• Neurobiological models suggest an interplay of genetic vulnerability (diathesis) and environmental stressors, but not all individuals with genetic risk develop suicidal behaviors 6.
• Genome-wide association studies have found some shared and some distinct loci between suicide risk and psychiatric disorders, supporting the existence of both overlapping and unique biological pathways 3 4.

What is the relationship between psychiatric disorders and suicide risk?

While psychiatric conditions, particularly mood disorders like depression, are major risk factors for suicide, not all individuals who die by suicide have identifiable psychiatric diagnoses. The current study's finding that about half of suicide cases lacked psychiatric diagnoses and genetic risk for such conditions highlights the need to look beyond traditional risk profiles.

• Family, twin, and adoption studies show heritability of suicide risk, but psychiatric diagnoses explain only part of the overall risk 2 3 4.
• Genetic risk scores for suicide attempts often overlap with those for major depression, but distinct genetic components are present, suggesting separate etiologies for some suicides 3 4.
• The stress-diathesis model supports a biological predisposition that interacts with environmental stressors, independent of current psychiatric illness 6.
• Some studies find that clinical and social risk factors, such as substance abuse and impulsivity, may contribute to suicide risk in the absence of psychiatric diagnoses 8.

Are there reliable warning signs or predictors for suicide?

The unpredictability of many suicide deaths is a recurring theme in research. While warning signs and behavioral changes can precede some suicides, a significant proportion of cases occur without clear or recognized signs, as the new study confirms.

• Many suicides, particularly those involving violent or less common methods, occur without the presence of traditional warning signs or behavioral changes 11 12 14.
• Affective or mood changes serve as warning signs for some attempters, but not all, making prediction of imminent risk challenging 12.
• The number and type of warning signs can differ by suicide method, with some methods (e.g., self-immolation) associated with fewer observable signs 11.
• Clinical guidelines emphasize the importance of distinguishing between risk factors and warning signs, but real-world prediction remains difficult 13 14.

What are the limitations of current biological and clinical risk assessments?

Despite advances in understanding the biological and genetic underpinnings of suicide, the predictive value of current biomarkers and clinical assessments remains limited. The new study further emphasizes the existence of at-risk individuals not captured by traditional approaches.

• Meta-analyses show that most biological markers, including genetic variants and cytokine levels, are weak predictors of suicide when considered independently 5 9.
• Risk assessments that focus only on known psychiatric or biological risk factors may miss substantial subsets of at-risk individuals, as highlighted by both the new study and existing literature 8 9.
• The complexity of suicide risk—spanning biological, psychological, and social domains—means that multifaceted approaches are needed for effective prevention 8.
• There is an ongoing need for research into new biomarkers, complex genetic interactions, and the role of environmental context in suicide risk 5 9.

Future Research Questions

Further research is needed to clarify the mechanisms underlying suicide risk in individuals without traditional warning signs or psychiatric diagnoses. Expanding our understanding of genetic, biological, and environmental contributors—and how these interact—will be crucial for improving prevention and intervention strategies.

Research Question	Relevance
What biological mechanisms contribute to suicide risk in the absence of psychiatric diagnosis?	Understanding non-psychiatric biological risk factors could help identify individuals currently missed by clinical screening and guide the development of new preventive interventions 6 7 10.
How do environmental and genetic factors interact to influence suicide risk?	Clarifying gene-environment interactions could reveal context-dependent risk profiles and explain why some individuals with genetic vulnerability do not develop suicidality 4 6 8.
Are there distinct biological or clinical subtypes of suicide deaths?	Identifying subtypes could enable tailored prevention strategies and improve risk assessment for groups not captured by current models 3 4 5.
Can novel biomarkers or genetic profiles improve prediction of suicide risk?	Developing better predictive tools may help identify at-risk individuals with no psychiatric history or warning signs, addressing a major gap in suicide prevention 5 9 10.
What are the roles of chronic pain, inflammation, and physical illness in suicide risk?	Physical health conditions may contribute to suicide risk through biological and psychosocial pathways, especially in individuals without psychiatric disorders 7 10.