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Genetics of the serotonergic system in suicidal behavior
Abstract
Genetic factors contribute to the risk of psychopathology in many psychiatric conditions, but the specific genes are yet to be identified. Neurotransmitter alterations are implicated in the etiology of psychopathology based, in part, on studies of neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem tissue. Identification of the altered receptors and enzymes serves to identify candidate genes of potential etiological significance. Polymorphisms in these genes can contribute to alterations in protein function in vivo that are part of the neurochemical underpinnings of psychopathologies such as major depressive disorder, psychoses, alcoholism, personality disorders, aggressive-impulsive traits, or suicidal behavior. Altered serotonergic function is implicated in the etiology and pathogenesis of several major psychiatric conditions. In particular, there is much evidence for an association of lower serotonergic function and suicidal behavior. Thus genes related to the serotonergic system are candidate genes worthy of study as part of the genetic diathesis for suicidal behavior. This review examines the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele), the 5-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) receptor (T102C) for their relationship to suicidal behavior. For the TPH gene, we found the less common U or A allele variant of the A779C polymorphism was associated with suicide attempt. Other studies have found the U allele to be associated with aggression and lower serotonergic function in vivo. A 44 base pair insertion/deletion in the 5' flanking promoter region of the 5-HTT gene may result in less 5-HTT expression and 5-HTT binding. We examined 220 cases postmortem and found no association between the promoter genotype and 5-HTT binding. We also found no association with major depressive disorder (MDD), suicide or pathological aggression, despite finding significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms for the 5-HT(1B) receptor at nucleotides 861 and 129. However, no association between either polymorphism and depression, suicide, aggression, or alcoholism was observed. There are two common polymorphisms for the 5-HT(2A) receptor gene in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT(2A) receptor itself is reported to be increased in suicide. Functional polymorphisms involving the promoter region that affect gene expression may explain this finding. Studies of candidate genes related to serotonergic function in brain are increasingly used to establish genetic alterations contributing to psychiatric illness. The most meaningful studies combine the study of candidate genes with direct measures of related proteins as well as psychopathology.
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“Abnormalities in dopaminergic, glutamatergic, GABAergic, and endocannabinoid systems have also been implicated in suicide.”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [33]
In the citing paper
“Alterations in CB1 receptor expression in the dorsolateral prefrontal cortex (PFC) of suicide victims, particularly among those with comorbid substance use, further implicate the endocannabinoid system in emotional regulation and stress response (32–34).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [33]
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Metadata
- Authors
- Arango, V., Huang, Y.-Y., Underwood, M. D., & Mann, J. J.
- Affiliations
- New York State Psychiatric Institute (US)
- Corresponding author
- Arango, Victoria
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 37
- Issue
- 5
- Pages
- 375-386
- ISSN
- 0022-3956 (ISSN-L)
- OpenAlex
- W2147421788
- Cited by
- 239
- References
- 122
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 8 · 2015: 14 · 2014: 12 · 2013: 6 · 2012: 19
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA09004, R01AA009004)
- National Institute of Mental Health (MH 62185, MH-40210, R01MH040210, P50MH062185)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- suicidal behavior, serotonergic system, candidate genes, tryptophan hydroxylase, serotonin transporter, 5-HTTLPR, 5-HT1B receptor, 5-HT2A receptor, genetic polymorphism, suicide attempts, major depressive disorder, aggression, serotonin transporter binding, prefrontal cortex, postmortem brain
- MeSH terms
- Brain, Carrier Proteins, Genotype, Humans, Membrane Glycoproteins, Monoamine Oxidase, Nerve Tissue Proteins, Polymorphism, Genetic, Risk Factors, Serotonin, Suicide, Tryptophan Hydroxylase, Membrane Transport Proteins, Receptor, Serotonin, 5-HT1A, Serotonin Plasma Membrane Transport Proteins
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