The tryptophan hydroxylase 1 ( TPH1 ) gene, schizophrenia susceptibility, and suicidal behavior: A multi-centre case-control study and meta-analysis (original) (raw)
Related papers
Tryptophan Hydroxylase-1 Gene Variants Associated with Schizophrenia
Biological Psychiatry, 2006
Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior, common features of the borderline personality disorder (BPD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. Two isoforms are known, TPH-1 and TPH-2. TPH-1 has been correlated to various psychiatric and behavioral disorders by gene polymorphism association studies. We aimed to determine whether specific TPH-1 haplotypes associate with BPD. A case-control design was employed. The control group included 98 women without psychiatric history. In all, 95 patients were included, all Caucasian women with a BPD diagnosis who had attempted suicide at least twice during their lifetime. Exclusion criteria were: (i) substance dependence; (ii) dementia or other irreversible organic brain syndromes; (iii) psychotic disorders or major depressive illness with melancholic features; (iv) life-threatening eating disorders. Six single-nucleotide polymorphisms (SNPs) were found at significant linkage disequilibrium across 23 kb of the TPH-1 gene in both patients and controls, suggesting a haplotype block structure. While no individual SNP showed association, several haplotypes associated with the BPD group. In particular, one six-SNP haplotype was absent from the control group while representing about one-quarter of all haplotypes in the BPD group (corrected P<10(-5)). A 'sliding window' analysis attributed the strongest disease association to haplotype configurations located between the gene promoter and intron 3. We conclude that TPH-1 associates with BPD in suicidal women. Our data support the expectation that haplotype analysis is superior to single locus analysis in gene-disease, case-control association studies.
The role of tyrosine hydroxylase gene variants in suicide attempt in schizophrenia
Neuroscience Letters, 2014
Evidence has shown that attempted suicide in psychiatric disorders is a complex interplay of genes and environment. Noradrenergic dysfunction due to abnormalities in the tyrosine hydroxylase (TH) gene has been implicated in the pathogenesis of suicidal behaviour in mood disorders. Also, suicide is a leading cause of mortality in schizophrenia. Recent evidence suggests that TH gene variants may also increase the risk of suicide attempts in schizophrenia patients,although the interaction with established clinical risk factors is unclear. This study aimed to identify TH gene variants at risk for suicide attempt in schizophrenia while accounting for the interaction between this gene and clinical risk factors . We performed analysis on four TH SNPs (rs11564717, rs11042950, rs2070762, rs689) and the common TCAT repeat (UniSTS:240639) for 234 schizophrenia patients (51 suicide attempters and 183 non-attempters). Clinical risk factors and ethnic stratification were included as covariates. Single marker analysis identified the SNP rs11564717 (p=0.042) and the TCAT (6) (p=0.004) as risk variants for suicide attempt. We also identified the haplotype A-A-A-G as a risk factor for suicide attempt (p=0.0025). In conclusion, our findings suggest that TH polymorphisms may contribute to the risk of attempted suicide in schizophrenia even after accounting for established clinical risk factors and ethnic stratification. Further larger scale studies are needed to confirm these findings and to understand the mechanisms underlying the role of TH gene variants in suicide attempt in schizophrenia.
American Journal of Medical Genetics, 2003
Previous studies testing the functional polymorphism in the promoter of the serotonin-transporter gene (5HTTLPR) in various psychiatric conditions have suggested that the association could be with an intermediate phenotype, impulsivity and/or violence rather than with a diagnosis. Schizophrenia is associated with a high risk of suicide, especially in patients with high impulsivity. We examined whether this polymorphism could be associated with violent suicide and/or impulsivity in schizophrenic patients. We genotyped the 5HTTLPR polymorphism in 185 unrelated schizophrenic patients from a French Caucasian population. The genotype frequencies significantly differed between patients who made violent suicide attempts and both, those who attempted suicide with a non-violent method (P = 0.013) and those who never attempted suicide (P = 0.026). The genotypes containing the low activity “short” allele was significantly more frequent in violent suicide attempters (P = 0.007) than in non-violent suicide attempters. No evidence was found for an association either with schizophrenia itself, when compared to gender and ethnically matched controls (n = 159) or with impulsivity, assessed using Barratt's Impulsivity Scale. Although replication studies are warranted, these results in schizophrenia further support the hypothesis that 5HTTLPR polymorphism is a risk factor for violent suicidal behavior. © 2003 Wiley-Liss, Inc.
TPH1 A218 allele is associated with suicidal behavior in Turkish population
Legal Medicine, 2016
Background: Serotonergic dysfunction is implicated in depression, psychiatric disorders and suicidal behaviors. The first and rate-limiting step in the synthesis of serotonin is catalyzed by tryptophan hydroxylase (TPH) which is encoded by TPH1 and THP2 genes. Genetic association studies have revealed contradictory results about the effect of the TPH1 A218C (rs1800532) polymorphism on suicidal behavior in different populations. Material and method: In this study, we investigated A218C polymorphism in 109 suicide attempters and 98 healthy controls. Socio-demographic characteristics of participants were obtained through questionnaire. DNA was extracted from peripheral blood and genotyping was performed by Real Time PCR. Fisher's exact test was used to evaluate the significance of the difference among the independent variables. Hardy-Weinberg equilibrium was tested using Pearson's goodness-of-fit chi-squared test. Results: The frequency of A allele was significantly higher in suicide attempters than controls (46.33% vs. 35.71%, p = 0.0357). However, there were no differences in genotype frequencies of this locus between participants having attempted suicide and controls (p > 0.05). Among males, frequencies of CC genotype and C allele were found to be significantly higher in controls (p = 0.0125, p = 0.0298). With regard to the female subjects and female controls, no significant association was detected between suicidal behavior and genotype/allele frequencies (p > 0.05). Conclusion: Our results provide evidence that A allele of TPH1 A218C polymorphism may be associated with suicidal behavior in Turkish population.
European Neuropsychopharmacology, 2006
A serotonin transporter gene linked polymorphic region (5-HTTLPR) has been investigated in several genetic association studies, including studies of schizophrenia and suicidality. The current study was designed to examine whether the new long (A/G) variant polymorphism of the 5-HTT gene may be associated with suicide attempts of 290 Caucasian schizophrenic patients. Among these patients, 92 had a history of suicide attempt. No association with history of suicide attempt was found in the multiallelic 5-HTTLPR ( p = 0.305), however we found significant association with the intron 2 VNTR polymorphism ( p = 0.018). When we performed a haplotype analysis, we found association between suicide attempt and haplotype distribution ( p = 0.031). These findings suggest that the intron 2 VNTR polymorphism in serotonin transporter gene may influence suicidal behaviour in schizophrenia. D
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2009
Genetic variation in the serotonin 2A receptor (HTR2A) has been associated with both schizophrenia and suicidal behavior. Our sample comprised 270 Irish high-density schizophrenia families (n=1408 subjects, including 755 with psychotic illness). Diagnoses were generated using a modified SCID. All patients who had at least one episode of psychosis were rated on the Operation Criteria Checklist for Psychotic Illness (OPCRIT). Lifetime history of suicidal ideation was determined from medical records and psychiatric interviews and was scored in the OPCRIT. Twelve SNPs were selected for study. Ten of these were tagSNPs derived from HapMap data, along with His452Tyr and T102C. We tested for association with psychotic illness as a whole, as well as stratified by the presence of suicidal ideation, using FBAT and PDTPHASE. Singlemarker as well as haplotype-based tests using a "sliding window" approach were performed. We observed several 2, 3, and 4 marker haplotypes near the 3′ end of the gene that were overtransmitted to psychotic subjects (.02≤P≤.04). His452Tyr was included in these haplotypes but was not itself significant. We also observed modest over-transmission of a 2-marker haplotype that included T102C (.04≤P≤.08), which was also not itself significant in single-marker analyses. There was no significant association in the subgroup of the sample with suicidal ideation. Because of multiple testing, these results do not provide support for HTR2A as a susceptibility gene for psychotic illness, or for suicidal ideation within psychotic illness.
BMC Psychiatry, 2014
Background: It is widely acknowledged that suicidal behavior (SB) has a genetic influence. As a consequence, molecular genetic studies have been mostly conducted on serotonergic genes. One of the most promising candidate genes of this system is tryptophan hydroxylase (TPH). Although there have been several positive studies associating TPH genes and SB, the evidence is not entirely consistent. Therefore, we performed a meta-analysis to gain a better understanding into this issue. Methods: The meta-analysis was conducted with 37 articles of genetic association studies of TPH-1 (A218C and A779C) and TPH2 (G-703 T, A-473 T and G19918A) genes. To analyze the association of these variants with SB we used the following models: allelic, additive, dominant and recessive. In addition, we performed a sub-group analysis by Caucasian and Asian populations using the same four models.