Cited by 241Neurotransmitter Receptor Influence on BehaviorSuicide and Self-Harm StudiesGenetic Associations and Epidemiology

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Genetics of the serotonergic system in suicidal behavior

Arango, Victoria, Huang, Yung-yu, Underwood, Mark D., Mann, J.John·2003·Journal of Psychiatric Research

DOI 10.1016/s0022-3956(03)00048-7

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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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Authors: Arango, V., Huang, Y.-Y., Underwood, M. D., & Mann, J. J.
Affiliations: New York State Psychiatric Institute (US)
Corresponding author: Arango, Victoria
ORCID: Arango, Victoria
Underwood, Mark D.
Mann, J.John
Venue: Journal of Psychiatric Research
Publisher: Elsevier BV
Published: 2003-09
Volume: 37
Issue: 5
Pages: 375-386
ISSN: 0022-3956 (ISSN-L)
DOI: 10.1016/s0022-3956(03)00048-7
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Genetics of the serotonergic system in suicidal behavior

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