Serotonin 2A receptor gene polymorphism is not associated with completed suicide

Ono, Hitoshi; Sato, Osamu; Nishiguchi, Naoki; Nishimura, Akiyoshi; Nushida, Hideyuki; Ueno, Yoshio; Maeda, Kiyoshi

doi:10.1016/s0022-3956(01)00015-2

Cited by 43 publications

(31 citation statements)

References 22 publications

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“…Our results confirm previous reports that genotype frequencies of 102T/C 5-HT 2A receptor gene polymorphism in mood disorders do not differ from healthy volunteers (Arranz et al, 1997;Bondy et al, 2000;Crawford et al, 2000;Mahieu et al, 1997;Minov et al, 2001;Tsai et al, 1999;Ono et al, 2001;Correa et al, 2002;Geijer et al, 2000). Nevertheless, we found an excess of the TC genotype in suicide attempters compared with nonattempters.…”

Section: Discussionsupporting

confidence: 91%

“…Greater 5-HT 2A binding has been reported in post-mortem brain tissue from individuals with major depression and suicide victims by some but not all studies (Stanley and Mann 1983;Mann et al, 1986;Hrdina and Du 2001;Kato et al, 1996;Ono et al, 2001;Hrdina et al, 1993;Arora and Meltzer 1989;Yates et al, 1990). Pandey et al (1995) found that higher prefrontal cortical 5-HT 2A binding was associated with greater gene expression in youth suicide.…”

Section: Introductionmentioning

confidence: 94%

“…A more recent meta-analysis demonstrated a stronger association with schizophrenia in Caucasians compared with other ethnic groups (Abdolmaleky et al, 2004). No association of genotype or allele frequencies is found with suicide or mood disorders (Arranz et al, 1997;Bondy et al, 2000;Crawford et al, 2000;Mahieu et al, 1997;Minov et al, 2001;Tsai et al, 1999;Ono et al, 2001;Correa et al, 2002;Geijer et al, 2000). Turecki et al (2003) found that higher 5-HT 2A binding in the brain is associated with the T102C polymorphism in the 5-HT 2A gene independently of suicide, although others disagree (Hrdina and Du, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Association of Serotonin 5-HT2A Receptor Binding and the T102C Polymorphism in Depressed and Healthy Caucasian Subjects

Khait

Huang

Zalsman

et al. 2004

Neuropsychopharmacol

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Serotonin 5-HT 2A receptor (5-HT 2A ) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT 2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT 2A binding kinetics (B max and K D ) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher B max in all subjects (F ¼ 3.53, df ¼ 2,211; p ¼ 0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F ¼ 7.56, df ¼ 2,60, p ¼ 0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. B max was not related to a diagnosis of mood disorders.The TT genotype appears associated with higher platelet 5-HT 2A B max in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Association of Serotonin 5-HT2A Receptor Binding and the T102C Polymorphism in Depressed and Healthy Caucasian Subjects

Khait

Huang

Zalsman

et al. 2004

Neuropsychopharmacol

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“…122 As completed suicides are more homogeneous in terms of higher lethality and are thought to be more influenced by serotonergic mechanisms than attempted suicides, 7 we and others examined whether one of the 5-HT2A receptor polymorphisms was associated with completed suicides, irrespective of the underlying clinical diagnosis. Neither the A-1438G nor the T102C polymorphism were associated with completed suicide in 151 Japanese, 123 131 Caucasian 124 or 68 Australian suicide victims. 125 However, one has to take into account that in none of these studies a psychological autopsy was available, and therefore no information about the proportion of depressed patients in these samples.…”

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confidence: 92%

Genetics of suicide

2006

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The concept that genetic factors contribute to the complex trait of suicidal behaviour has stimulated much work aimed at identifying susceptibility genes. So far molecular genetic studies focused on the serotonergic pathway as the intent to die and the lethality of suicide acts were related to the serotonergic system. Two genes have so far emerged as being involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C) of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal behaviour, but in violent and repeated suicide attempts. The data have further shown that the MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is not related to suicide but might induce violent methods in subjects with other suicide risk factors. Predominantly negative were the findings with any type of the serotonin receptors and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the dopaminergic receptors. This paper reviews the status of current knowledge in this area, points to the weakness of the investigations and presents new approaches beyond the serotonergic system.

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“…13 In an association study, Du et al reported that the C allele of the T102C polymorphism, which is almost completely in disequilibrium with the A-1438G polymorphism, 14 was associated with suicidal ideation in major depressive disorders, 15 although no association was found between these polymorphisms and suicidal behavior itself. 12,16,17 Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis and has a major function in regulating the serotonergic system. However, TPH activity as a pre-synaptic serotonergic marker has not been measured in the postmortem brain of suicide victims.…”

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confidence: 99%

Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls

et al. 2002

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Keywords: tryptophan hydroxylase (TPH); serotonin 2A receptor (5HT2A receptor); polymorphism; suicide; postmortem brain study; western blot; receptor binding assay Several lines of evidence suggest that a partly genetically controlled serotonergic dysfunction is involved in the biological pathogenesis of suicide. In this study, we measured tryptophan hydroxylase (TPH) immunoreactivity as a pre-synaptic marker, and serotonin receptor 2A (5HT2A receptor) density as a post-synaptic marker in the serotonergic system in 10 postmortem brains of suicide victims. We also examined whether TPH gene polymorphisms (A218C and A-6526G polymorphisms) could affect TPH immunoreactivity and 5HT2A receptor gene polymorphism (A-1438G polymorphism) could affect 5HT2A receptor density in 28 postmortem brain samples. No significant differences were found in TPH immunoreactivity or 5HT2A receptor density between suicide victims and controls. The AA genotype of the A218C polymorphism of the TPH gene showed higher TPH immunoreactivity along with lower 5HT2A receptor density than did any other genotypes in the postmortem brains of both suicide victims and controls. Our findings suggest that the A218C polymorphism of the TPH gene can be expected to provide new insights not only for neurobiological studies of suicide, but also for research into the behavioral characteristics that may be associated with serotonergic dysfunction. Molecular Psychiatry (2002) 7, 1127-1132. doi:10.1038/ sj.mp.4001150 Abnormalities in the serotonergic system have been found in suicides. 1 A reduced concentration of 5-hydroxyindoleacetic acid, the principal metabolite of serotonin, has been identified in the cerebrospinal fluid of suicide attempters. 2,3 A blunted prolactin response to fenfluramine, which indicates central serotonergic hypofunction, 4 has also been demonstrated in suicide attempters. 5 These findings seem to be independent of psychiatric diagnoses and to correlate with the lethality of suicide attempts.Many, although not all, postmortem studies of suicide victims have reported an increase in 5HT2A receptor density in the prefrontal cortex of suicide victims. [6][7][8][9] It is thought that these findings may result from mechanisms such as adaptive or compensatory 5HT2A receptor up-regulation secondary to reduced pre-serotonergic neurotransmission which might be under genetic control. These conclusions are based on the results of studies of family, twins and adoption, which suggest that genetic factors may be involved in the etiology of suicidal behavior. 10,11 Recently, Turecki et al 12 have reported that the A-1438G polymorphism of the 5HT2A receptor gene significantly affects the 5HT2A receptor in the prefrontal cortex (Brodmann's area 9), but another study was unable to replicate their results. 13 In an association study, Du et al reported that the C allele of the T102C polymorphism, which is almost completely in disequilibrium with the A-1438G polymorphism, 14 was associated with suicidal ideation in major depressive disorders, 15 although...

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Serotonin 2A receptor gene polymorphism is not associated with completed suicide

Cited by 43 publications

References 22 publications

Association of Serotonin 5-HT2A Receptor Binding and the T102C Polymorphism in Depressed and Healthy Caucasian Subjects

Association of Serotonin 5-HT2A Receptor Binding and the T102C Polymorphism in Depressed and Healthy Caucasian Subjects

Genetics of suicide

Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls

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