Tryptophan Hydroxylase Genotype Research Articles

Genetic polymorphisms in the serotonergic system and symptom clusters of major depressive disorder

It has been suggested that the symptoms of major depressive disorder (MDD) are composed of some clusters, which are linked to distinct genetic mechanisms. The purpose of this study was to examine the associations of genetic polymorphisms in the serotonergic system with three factors of the Montgomery-Åsberg Depression Rating Scale (MADRS), i.e., dysphoria, retardation, and vegetative symptoms. The subjects were 132 Japanese patients of MDD. The genotypes of tryptophan hydroxylase 218A/C, serotonin transporter gene-linked polymorphic region (5HTTLPR), and 5HT2A receptor -1438G/A polymorphisms were determined by PCR methods. Statistical analyses were performed by the multiple regression analysis. The A allele of 5HT2A polymorphism was associated with higher vegetative scores (p=0.001) and total MADRS scores (p=0.005), while the S allele of 5HTTLPR was related to higher dysphoric scores (p=0.012). The tryptophan hydroxylase genotype was not related to any factor scores or total MADRS scores. The sample size was relatively small, and the subjects were composed of Japanese only. This study suggests that the genetic polymorphisms in 5HT2A receptor and serotonin transporter are linked to discrete symptom clusters of MDD.

No association between the TPH A218C polymorphism and personality traits in Japanese healthy subjects

It has been suggested that the central serotonergic activity is implicated in personality traits. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. In the present study, the association between the TPH A218C polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) was examined in 345 Japanese healthy subjects. The TPH A218C polymorphism was determined by a PCR-RFLP method. There were no significant differences in the seven dimension scores of TCI among the A/A, A/C, and C/C genotype groups by the one-way ANOVA. There was a significant negative correlation between age and the NS scores. Females showed significantly higher scores of HA, RD, and ST, and significantly lower scores of SD than males. The multiple regression analysis using age, gender, and the TPH genotype as independent variables also showed no significant association between any dimension score and the genotype. The present study thus suggests that the TPH A218C polymorphism does not affect personality traits in Japanese healthy subjects.

Investigation of A218C tryptophan hydroxylase polymorphism: association with familial suicide behavior and proband's suicide attempt characteristics

According to WHO, suicide accounts for about 1,000,000 deaths worldwide every year. In view of these dramatic data, several studies have tried to identify possible biological mechanisms and markers of suicide. Genes encoding for proteins involved in the serotonergic transmission are major candidates in association studies of suicidal behavior. The gene that codes for tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, is one of these candidates. Two polymorphisms in intron 7 of this gene (A218C and A779C) have been described, but their role in suicidal behavior remains uncertain. TPH A218C polymorphism was analyzed in a sample of 248 psychiatric patients and 63 healthy controls. In addition, at least one close relative member was interviewed to assess family suicidal behavior history. Our research confirmed that a positive history of suicide attempts in a family member is associated with the chance of an individual to attempt suicide. Furthermore, we demonstrated that familial suicide attempts are more lethal and frequently more violent. We were not able to find significant differences of the TPH genotype frequencies between patients and controls. The TPH A218C genotypes were not associated with a history of suicide attempt and the lethality of the most lethal lifetime suicide attempt and suicide attempt method. The authors conclude that the A218C polymorphism of the TPH gene may not be a susceptibility factor for suicidal behavior in this group of psychiatric patients but confirm that a family suicidal behavior history increases the proband's suicide attempt risk.

Interaction between the Tryptophan Hydroxylase Gene and the Serotonin Transporter Gene in Schizophrenia but Not in Bipolar or Unipolar Affective Disorders

Increasing focus is being given to identify possible combinations of genes related to specific clinical phenotypes. In our sample of 814 patients comprising 114 with schizophrenia, 416 with bipolar affective disorder and 284 with unipolar affective disorder, we studied interactions between the tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR), and the dopamine receptor (DRD4) genes in relation to five major psychiatric symptomatology scores. There was significant interaction between the TPH and the 5-HTTLPR genes. With an increasing number of short (s) alleles of 5-HTTLPR, the scores for delusions, disorganization and negative symptoms were significantly decreasing among subjects having the TPH genotype AA but increasing among subjects having the TPH genotype AC, yielding the highest scores for the combinations AA × ll and AC × ss. Since high scores on just delusions, disorganization and negative symptoms but low scores on excitement and depression were found among subjects with schizophrenia, we conducted comparisons among the three diagnostic categories and controls as regards the combined TPH × 5-HTTLPR genotype distribution. Schizophrenia subjects had a significantly different distribution of the genotype combination for TPH × 5-HTTLPR as compared to 241 controls or to unipolar or bipolar subjects, and had significantly higher frequencies of AA × ll and of AC × ss. Thus, an interaction between TPH and 5-HTTLPR genes constitutes susceptibility to schizophrenia, thereby yielding apparent relationships between the major psychiatric symptomatology scores and genotype combinations in samples that are obtained by pooling schizophrenia with other diagnostic categories.

P.3.045 Genetic variants of the 5HT2A and D2 receptor genes and weight change during olanzapine treatment

It has been suggested that the symptoms of major depressive disorder (MDD) are composed of some clusters, which are linked to distinct genetic mechanisms. The purpose of this study was to examine the associations of genetic polymorphisms in the serotonergic system with three factors of the Montgomery-Åsberg Depression Rating Scale (MADRS), i.e., dysphoria, retardation, and vegetative symptoms.The subjects were 132 Japanese patients of MDD. The genotypes of tryptophan hydroxylase 218A/C, serotonin transporter gene-linked polymorphic region (5HTTLPR), and 5HT2A receptor -1438 G/A polymorphisms were determined by PCR methods. Statistical analyses were performed by the multiple regression analysis.The A allele of 5HT2A polymorphism was associated with higher vegetative scores (p = 0.001) and total MADRS scores (p = 0.005), while the S allele of 5HTTLPR was related to higher dysphoric scores (p = 0.012). The tryptophan hydroxylase genotype was not related to any factor scores or total MADRS scores.The sample size was relatively small, and the subjects were composed of Japanese only.This study suggests that the genetic polymorphisms in 5HT2A receptor and serotonin transporter are linked to discrete symptom clusters of MDD.

The TPH intron 7 A218C polymorphism and TCI dimension scores in alcohol-dependent patients: hints to nonspecific psychopathology

Aims A linkage of certain alleles of the tryptophan hydroxylase (TPH) intron 7 A218C polymorphism to suicidality and antisocial behaviour has been described. The aim of our study was to find any association between dimensions of the Temperament and Character Inventory (TCI) indicating impulsivity and the TPH polymorphism alleles in unselected alcohol-dependent patients and age-matched controls. Methods We examined 159 alcohol-dependent patients and 161 controls with the TCI and genotyped them for the TPH intron 7 A218C polymorphism alleles. Results Although homozygous TPH genotypes were found more often in alcohol-dependent patients than in controls, an association between TCI dimensions and TPH alleles was not observed in the complete sample. Alcohol-dependent patients, however, scored significantly higher for harm avoidance (HA) and lower for self-directedness (SD) than controls regardless of TPH genotype. Among controls, for those with the A/A genotype, harm avoidance was as high as in the group of alcohol-dependent patients, persistence (P) in that genotype was significantly lower than for all other genotypes in the patient and control group. Conclusion Even if there is no association between TCI dimensions and TPH genotype in our sample, hints to nonspecific psychopathology in connection with the A/A genotype are found.

P.2.004 Statistical models for population heterogeneityin epidemiological longitudinal studies: Person-centred latent class analysis to identity casemix groups in the Turkish schizophrenia outpatient health outcomes study

A linkage of certain alleles of the tryptophan hydroxylase (TPH) intron 7 A218C polymorphism to suicidality and antisocial behaviour has been described. The aim of our study was to find any association between dimensions of the Temperament and Character Inventory (TCI) indicating impulsivity and the TPH polymorphism alleles in unselected alcohol-dependent patients and age-matched controls.We examined 159 alcohol-dependent patients and 161 controls with the TCI and genotyped them for the TPH intron 7 A218C polymorphism alleles.Although homozygous TPH genotypes were found more often in alcohol-dependent patients than in controls, an association between TCI dimensions and TPH alleles was not observed in the complete sample. Alcohol-dependent patients, however, scored significantly higher for harm avoidance (HA) and lower for self-directedness (SD) than controls regardless of TPH genotype. Among controls, for those with the A/A genotype, harm avoidance was as high as in the group of alcohol-dependent patients, persistence (P) in that genotype was significantly lower than for all other genotypes in the patient and control group.Even if there is no association between TCI dimensions and TPH genotype in our sample, hints to nonspecific psychopathology in connection with the A/A genotype are found.

Intronic polymorphism of tryptophan hydroxylase and serotonin transporter: indication for combined effect in predisposition to suicide.

Indices of disturbed serotonergic neurotransmission are the most robust biological findings in suicide. Tryptophan hydroxylase (TPH) and 5-hydroxytryptamine 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 = 0.0156), with a clear dose-effect of the suspected ("lower activity") genotypes (p = 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.

P.5.032 Involvement of 5-HT1 and 5-HT2 receptor in regulation of methamphetamine self-administration in rats

It has been suggested that the central serotonergic activity is implicated in personality traits. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. In the present study, the association between the TPH A218C polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) was examined in 345 Japanese healthy subjects. The TPH A218C polymorphism was determined by a PCR-RFLP method. There were no significant differences in the seven dimension scores of TCI among the A/A, A/C, and C/C genotype groups by the one-way ANOVA. There was a significant negative correlation between age and the NS scores. Females showed significantly higher scores of HA, RD, and ST, and significantly lower scores of SD than males. The multiple regression analysis using age, gender, and the TPH genotype as independent variables also showed no significant association between any dimension score and the genotype. The present study thus suggests that the TPH A218C polymorphism does not affect personality traits in Japanese healthy subjects.

Allelic Variants of the Tryptophan Hydroxylase (A218C) and Serotonin 1B Receptor (A-161T) and Personality Traits

Human personality traits have a considerable hereditary component, and central serotonergic activity is implicated in the personality factors of the Tridimensional Personality Questionnaire (TPQ). Our population-based association study tested the hypothesis that the tryptophan hydroxylase (TPH) A218C and serotonin 1B receptor (HTR1B) A-161T polymorphisms were associated with TPQ personality trait scores in a sample population of 209 young healthy Chinese. No significant differences were demonstrated comparing scores of subjects bearing different TPH or HTR1B genotypes; however, a trend for difference in the novelty seeking score comparing TPH genotype groups was determined for the male population. Our negative findings suggest that the TPH A218C and HTR1B polymorphisms do not play major roles in the determination of TPQ personality traits.

A dimensional impulsive-aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: a pilot study in well-characterized impulsive inpatients.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, and association and linkage studies of its variants in suicidal and impulsive-aggressive behavior have brought conflicting results. This pilot study was designed to investigate whether TPH A218C genotypes could be associated with impulsive behavioral tendencies (IBTs) in consecutively admitted nonpsychotic nonorganic inpatients. Patients (20 females and 34 males; age, 38.8 +/- 11.8) did not differ from healthy nonimpulsive controls (16 females and 11 males; age, 35.2 +/- 10.2) regarding TPH genotypes, but in the patients, the number of IBT was related to the presence of the 218C allele. It was concluded that impulsive-aggressive behavior may be associated with the TPH genotype in well-characterized impulsive patients and that the present results stress the importance of considering impulsiveness-aggressiveness in studies investigating the relationship between suicidal behavior and TPH genotypes.

Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder

Background: Abnormalities in functioning of the central serotonergic system have been implicated in the pathogenesis of depressive illness and suicidal behavior. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, therefore, it may play an important role in regulation or control of serotonin functions. The aim of the present investigation was to determine whether there is an association between TPH gene polymorphism and major depression, particularly in patients with suicidal ideation. Methods: A total of 135 unrelated patients suffering from major depressive disorder and 196 normal unrelated controls were included in the study. All controls and patients were Caucasian. A biallelic polymorphism at the tryptophan hydroxylase locus was genotyped. Results: No significant difference between controls and depressed subjects in TPH gene polymorphism was detected. There was no association between TPH gene polymorphism and suicidal ideation. Total HAMD scores were not different between the genotypes or alleles in patients. However, among the HAMD clusters, somatic anxiety was significantly associated with TPH genotypes and alleles in that patients with 218A/A genotype had a significantly higher somatic anxiety scores compared to other genotypes. Limitation: Potential confounding effect of population stratification can not be excluded. The functional relevance of the TPH gene 218A/C polymorphism is, at present, uncertain. Conclusion: The polymorphism in serotonergic system related genes may be associated with depressive symptoms in major depressive disorder. The results suggest that analysis of clusters that narrow down the phenotype may be more suitable in genetic studies of major depressive illness.

Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders

The human tryptophan hydroxylase (TPH) gene, the rate-limiting enzyme in serotonin biosynthesis, was localized on human chromosome 11p14–p15.3. Variation within intron 7 of the TPH gene was found to influence serotonin metabolism in the brain. To explore the possible role of TPH in the pathogenesis of schizophrenic disorders, we genotyped the TPH A218C polymorphism in 196 schizophrenic patients and 251 controls. The results demonstrated that genotype distribution was significantly different between schizophrenic patients and control subjects ( P=0.002). No association was found between TPH genotypes and suicidal history in schizophrenic patients ( P=0.239). The positive finding in this study suggests that the TPH 218A allele is a risk factor for schizophrenic disorders or is in linkage disequilibrium with the putative schizophrenia susceptibility locus in Han Chinese population.

An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder.

Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed.

A tryptophan hydroxylase gene marker for suicidality and alcoholism.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Low turnover rate of this monoamine neurotransmitter is associated with impaired impulse control. We previously reported that, in Finns, TPH genotype was associated with suicidality, a pathophysiological mechanism that may involve impaired impulse control. Association and sib-pair linkage analyses of a polymorphism in intron 7 of the TPH gene with suicidality, alcoholism, and the Karolinska Scales of Personality were conducted in 804 Finnish alcoholic offenders, controls, and their relatives, in a sample that included 369 sib pairs. The association of the TPH 17 779C (L) allele to suicidality in impulsive offenders reported previously was replicated in a new group of Finnish offenders (P=.001, n=122). The intron 7 variant in the TPH gene showed significant evidence for linkage to suicidality (P=.006 in unaffected sib pairs), severe suicide attempts (P=.006 in unaffected sib pairs; regression: P=.01), alcoholism (P=.003 in unaffected sib-pairs; regression: P=.02), and Karolinska Scales of Personality socialization score (regression: P=.002). The status of the TPH A779C allele as a marker for suicidality was replicated and linkage with alcoholism and Karolinska Scales of Personality socialization score was also observed. A functional variant(s) in or close to the TPH gene may predispose individuals to suicidality and other behaviors thought to be influenced by serotonin.

No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and non-suicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders.

No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and nonsuicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:245–247, 1998. © 1998 Wiley-Liss, Inc.

Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study.

To assess the relationship between two phenotypes in an extremely well-characterized population of personality disorder patients-impulsive aggression and prolactin response to fenfluramine-and tryptophan hydroxylase (TPH) genotype, TPH genotype (at an intronic polymorphic site) and prolactin response to fenfluramine were assessed in 40 Caucasian patients with personality disorder. Impulsive aggression was assessed by using the Buss-Durkee Hostility Inventory (BDHI). Twenty-one male patients with the "LL" genotype had higher BDHI scores than men with the "UL" or the "UU" genotype. No relationship between genotype and prolactin response to fenfluramine was found. It was concluded that impulsive-aggressive behavior in male personality disorder patients may be associated with the TPH genotype.

Association Between the Tryptophan Hydroxylase Gene and Manic-depressive Illness

Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts. The TPH intron 7 A218C polymorphism was determined using a polymerase chain reaction-based method in DNA samples from 152 patients with bipolar disorder and 94 healthy control subjects. There was a significant association between TPH genotypes and manic-depressive illness. Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior. This result suggests the involvement of the TPH gene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.

Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients.

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.