Suicide attempts and the tryptophan hydroxylase gene (original) (raw)
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Variability of the tryptophan hydroxylase gene: Study in victims of violent suicide
Psychiatry Research, 2005
Tryptophan hydroxylase (TPH), the enzyme controlling serotonin synthesis, is considered to be a potential contributor to the biological substrate of suicide. The association of the promoter (À7065CT) and intron 7 (218AC) polymorphisms, and the related haplotype, of the Tph1 gene with suicidal behavior was investigated in a sample of 160 victims of violent suicide and 284 healthy controls. All individuals were males of Croatian (Slavic) origin. Allele frequencies of both polymorphisms in Croatian controls were similar to control values reported for other European populations. Alleles at the two loci demonstrated highly significant linkage disequilibrium. No differences between controls and victims for the Tph1 genetic variation, either at single loci, or at a haplotypic level, were demonstrated, albeit there was a tendency, not reaching statistical significance, towards an increase of the intron 7CC genotype in the suicide group. Negative association results on the individual Tph1 loci, in accordance with the majority of previous reports, confirmed the lack of their major effect also in the Slavic ethnicity. Haplotypic results, on the other hand, opposing the previous positive finding, point to the possible influence of ethnicity (or gender) on the association between the Tph1 gene polymorphism and suicide.
The American journal of psychiatry, 1997
This study was designed to test the hypothesis that serotonin-system-related genes may be correlated with suicide risk. Fifty-one unrelated Caucasian inpatients with major depression, with or without a history of suicidal acts, were genotyped for a biallelic polymorphism at the tryptophan hydroxylase locus. The less common tryptophan hydroxylase U allele occurred with greater frequency in the patients who had attempted suicide. A logistic regression analysis confirmed an association between tryptophan hydroxylase genotype and lifetime history of suicide attempts. Serotonergic-system-related genes may influence the risk of suicide in persons with major depression.
Journal of Neural Transmission, 2004
Indices of disturbed serotonergic neurotransmission are the most robust biological findings in suicide. Tryptophan hydroxylase (TPH) and 5hydroxytryptamine transporter (5HTt) are the main regulators of 5HT signaling. Owing to the assumed functionality of intronic polymorphisms of TPH (218AC) and 5HTt (VNTR-2) genes, we investigated frequencies of concurrence of the TPH and 5HTt genotypes containing ''lower activity'' alleles (CC and 1010, respectively), in 192 suicide victims and 377 controls. Significant differences in frequencies of 5HTt and TPH genotype combinations were found between suicide victims and control subjects (p ¼ 0.0156), with a clear dose-effect of the suspected (''lower activity'') genotypes (p ¼ 0.0046). Concurrent presence of the two, allegedly transcriptionally less active, variants of these genes seems to be in some kind of relation to the increased susceptibility to suicide.
Functional promoter polymorphism of the neuronal isoform of tryptophan hydroxylase (Tph2) in suicide
Psychiatry Research, 2011
The association between suicide and G-703T polymorphism of the tryptophan hydroxylase 2 (Tph2), the rate limiting enzyme in the biosynthesis of the neurotransmitter serotonin, was studied in a sample of 291 suicide victims and 280 healthy subjects of Croatian origin. No significant differences were found between the groups. Obtained results do not support involvement of the investigated polymorphism in the susceptibility to suicide completion.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2009
While there is some preliminary evidence that the tryptophan hydroxylase I (TPH1) polymorphisms are related to Borderline Personality Disorder (BPD), it is not clear if this association is due to the high rates of suicidal behavior in this patient group. Because of the reported association between TPH1 polymorphisms and suicidal behavior, determining whether TPH1 is related to BPD independent of suicidal behavior is of particular importance. One hundred patients diagnosed with BPD and 101 healthy controls were genotyped for TPH1 intron 7 A218C polymorphism and assessed for impulsiveness and hostility. The BPD patient group had a higher frequency of A allele carriers (AA/AC genotypes) than the control group (c 2 ¼ 6.12, df ¼ 1, P ¼ 0.01), and differed by genotype frequencies (P ¼ 0.03). Suicide attempter status in the patient group was not related to genotype. Logistic regression analysis controlling for age and gender predicted BPD diagnosis from TPH1 allele group (AA/AC vs. CC, P ¼ 0.03), and TPH1 heterozygotes (AC) appeared to have the highest risk for BPD (P ¼ 0.03). In the full sample, participants with the AC genotype had higher impulsiveness and hostility scores. However, TPH1 did not predict these traits in either of the groups independently, suggesting the association may be an artifact of the association between TPH1 and BPD. Results suggest that the A allele of the tryptophan hydroxylase-1 A218 polymorphism may be associated with BPD, and that it does not appear to be related to suicidal behavior in this population. An aspect of BPD pathology may be due to serotonergic dysfunction.
American Journal of Medical Genetics, 2001
The association of suicidality with polymorphism A218C in intron 7 of tryptophan hydroxylase (TPH) gene remains controversial. The aim of this study was to use familybased methods to examine this association in adolescents in order to eliminate the difficulty of sampling a control group from the same ethnic population. Eighty-eight inpatient adolescents who recently attempted suicide were assessed by structured interview for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, aggression, and depression. DNA samples were collected from all subjects, from both biological parents of 40 subjects and from one parent of 9 subjects; TPH allele frequencies were calculated and tested for association to phenotype, stratified by severity, using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) methods (n ¼ 49). The frequencies were also compared for all the Jewish subjects (n ¼ 84) to the known frequencies of these alleles in healthy Jewish populations. There was no significant allelic association of A218C polymorphism with suicidal behavior or other phenotypic measures according to the HRR method (chi-square ¼ 0.094; P ¼ 0.76), the TDT (chisquare ¼ 0.258; P ¼ 0.61), or association analysis to known population frequencies (chi-square ¼ 1.667, P ¼ 0.19 for Ashkenazi, and chi-square ¼ 0.810, P ¼ 0.37 for non-Ashkenazi). Analysis of variance with the Scheffè test demonstrated a significant difference between CC and AA genotypes in suicide risk and depression among the patients (n ¼ 88). The findings suggest that polymorphism A218C has no major relevance to the pathogenesis of adolescent suicidal behavior, but may have a subtle effect on some related phenotypes.
Journal of Psychiatric Research, 2010
Bipolar disorder (BD) is a severe psychiatric illness characterized by the occurrence of elevated mood alternating with depressive episodes, having a estimated lifetime prevalence of 0.4-1.6% using DSM-IV criteria. Disturbances of the central serotonergic system has been associated with the pathophysiology of affective disorders and suicidal behavior. Tryptophan hydroxylase 2 (TPH2) which is a rate limiting enzyme in the serotonin synthesis is considered an important candidate gene associated with psychiatric disorders. Our sample consisted of 527 subjects (303 diagnosed with bipolar disorder and 224 healthy controls) which were genotyped for eight tagSNPs (rs4448731, rs4565946, rs11179000, rs7955501, rs10506645, rs4760820, rs1487275 and rs10879357) covering the whole gene of the human TPH2. Statistical analyses were performed using UNPHASED version 3.0.12 and Haploview Ò . Single markers, genotype and haplotype association analysis did not show significant genetic association with bipolar disorder or suicidal behavior. Our findings do not support the association between diagnosis of BD or suicidal behavior and TPH2 polymorphisms.
Genetics of the serotonergic system in suicidal behavior
Journal of Psychiatric Research, 2003
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 0 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. #
Neuropsychobiology, 2001
Objective: To evaluate the relationship of the tryptophan hydroxylase (TPH) genotype to suicidality by the study of surviving monozygotic (MZ) cotwins of twins who committed suicide. Method: Twenty-four surviving Swedish MZ twins whose MZ cotwins had committed suicide were compared to 158 demographically sampled Swedish general population controls for TPH alleles. We also examined serotonin transporter alleles. Results: The living MZ cotwins of suicide victims had a significantly higher TPH 17 779C allele frequency than controls. No significant difference was observed for serotonin transporter alleles. Conclusion: These results, in a small sample, suggest the possibility that the 17 779C allele of the TPH gene may be associated with an increased risk of suicide. Further studies in larger samples are needed.