Candidate endophenotypes for genetic studies of suicidal behavior
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Twin, adoption, and family studies have established the heritability of suicide attempts and suicide. Identifying specific suicide diathesis-related genes has proven more difficult. As with psychiatric disorders in general, methodological difficulties include complexity of the phenotype for suicidal behavior and distinguishing suicide diathesis-related genes from genes associated with mood disorders and other suicide-associated psychiatric illness. Adopting an endophenotype approach involving identification of genes associated with heritable intermediate phenotypes, including biological and/or behavioral markers more proximal to genes, is an approach being used for other psychiatric disorders. Therefore, a workshop convened by the American Foundation for Suicide Prevention, the Department of Psychiatry at Columbia University, and the National Institute of Mental Health sought to identify potential target endophenotypes for genetic studies of suicidal behavior. The most promising endophenotypes were trait aggression/impulsivity, early-onset major depression, neurocognitive function, and cortisol social stress response. Other candidate endophenotypes requiring further investigation include serotonergic neurotransmission, second messenger systems, and borderline personality disorder traits.
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Current research on suicidality is limited by small sample sizes, a primary focus on adult populations, and difficulty differentiating suicidal behavior from co-occurring mood disorders.
“Current research, however, is limited by small sample sizes, a primary focus on adult populations, and the difficulty of differentiating suicidal behavior from co-occurring mood disorders (8).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [8]
The Methodological Issues section (page not available) says genetic studies of suicidal behavior face challenges and require large samples; the Heritability section discusses separating suicidal behavior from psychiatric disorders by controlling for them. The copy does not establish that current studies generally have small samples or focus primarily on adults, and it does not specifically identify co-occurring mood disorders as the source of the differentiation difficulty. (LLM, conf=0.78)
Experimental — accuracy not yet measuredKey mediating factors between distal factors and proximal factors include personality traits.
“Key mediating factors between distal factors and proximal (also known as precipitating) factors include personality traits 62 .”
From Suicide and suicide risk (2019) · cites this paper as [62]
The Abstract and 'Defining Endophenotypes for Suicidal Behavior' section identify impulsive-aggressive traits as intermediate phenotypes relevant to suicidal behavior. They do not describe personality traits as mediating between distal and proximal (precipitating) factors; the intermediate relationship described is between genes and disease. Page numbers were not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredTo date, few biological targets have been associated with the active suicide crisis or immediate suicide risk.
“While candidate endophenotypes have been suggested (29), to date, few biological targets have been associated with the active suicide crisis or immediate suicide risk, which presents an impediment to developing new treatments and enabling precision psychiatry.”
From New methods for assessing rapid changes in suicide risk (2021) · cites this paper as [29]
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No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover
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Self-citationMeasurement of aggression in psychiatric patients
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- [40]Langley K Marshall L van den BM Thomas H Owen M O’Donovan M Thapar A Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD Am J Psychiatry 161 2004 133 138 14702261
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“Current research, however, is limited by small sample sizes, a primary focus on adult populations, and the difficulty of differentiating suicidal behavior from co-occurring mood disorders (8).”
- Authors
- Mann, J. J., Arango, V. A., Avenevoli, S., Brent, D. A., Champagne, F. A., Clayton, P., Currier, D., Dougherty, D. M., Haghighi, F., Hodge, S. E., Kleinman, J., Lehner, T., McMahon, F., Mościcki, E. K., Oquendo, M. A., Pandey, G. N., Pearson, J., Stanley, B., Terwilliger, J., & Wenzel, A.
- Affiliations
- New York State Psychiatric Institute (US)
- Columbia University (US)
- National Institutes of Health (US)
- American Foundation for Suicide Prevention (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Illinois Chicago (US)
- University of Pennsylvania (US)
- Corresponding author
- Mann, J. John
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 65
- Issue
- 7
- Pages
- 556-563
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3271953
- OpenAlex
- W2128006992
- Cited by
- 398
- References
- 100
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 13 · 2023: 10 · 2022: 18 · 2021: 23 · 2020: 21 · 2019: 19 · 2018: 36 · 2017: 19 · 2016: 36 · 2015: 31 · 2014: 41 · 2013: 22 · 2012: 28
- FWCI
- 30.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (Z01MH002903, R01MH048514, R01MH084995)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- suicidal behavior, endophenotypes, neurocognitive function, serotonergic neurotransmission, second messenger signaling, borderline personality traits, genetic susceptibility
- MeSH terms
- Suicide Prevention, Aggression, Borderline Personality Disorder, Brain, Cognition Disorders, Major Depressive Disorder, Humans, Hydrocortisone, Impulsive Behavior, Phenotype, Serotonin, Stress, Psychological, Suicide, Attempted, Second Messenger Systems, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Epigenesis, Genetic
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