TPH2 Polymorphisms Research Articles

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the chinese Han population

BackgroundLifelong premature ejaculation (LPE) is one of the most common ejaculatory dysfunctions in men. The serotonin (5-HT) synthesis rate-limiting enzyme (TPH2) and receptor (HTR1A) in the 5-HT regulatory system may play a key role in the pathogenesis of LPE. However, there are few studies on the effects of TPH2 and HTR1A polymorphisms on LPE risk. We speculated that TPH2 and HTR1A polymorphisms may affect the occurrence and development of LPE in the Chinese Han population.MethodsIn this study, 91 patients with LPE and 362 normal controls aged 18 to 64 years were enrolled in the male urology department of Hainan General Hospital in China from January 2016 to December 2018. The SNPs in HTR1A and TPH2, which are related to 5-HT regulation, were selected as indexes to genotype the collected blood samples of participants. Logistic regression was used to analyze the correlation between SNPs of HTR1A and TPH2 with LPE susceptibility, as well as the relationship with leptin, 5-HT and folic acid levels.ResultsThe results revealed that HTR1A-rs6295 increased LPE risk in recessive model. Rs11178996 in TPH2 significantly reduced susceptibility to LPE in allelic (odds ratio (OR) = 0.68, 95% confidence interval (95% CI) = 0.49–0.96, p = 0.027), codominant (OR = 0.58, 95% CI = 0.35–0.98, p = 0.040), dominant (OR = 0.58, 95% CI = 0.36–0.92, p = 0.020), and additive (OR = 0.71, 95% CI = 0.52–0.98, p = 0.039) models. Grs11179041Trs10879352 could reduce the risk of LPE (OR = 0.44, 95% CI = 0.22–0.90, p = 0.024) by haplotype analysis.ConclusionHTR1A-rs6295 and TPH2-rs11178996 are associated with LPE risk in the Chinese Han population based on the finding of this study.

HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV).

Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, LG/LG, and S/LG) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the Chinese Han population

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the Chinese Han population

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the Chinese Han population

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the Chinese Han population

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the Chinese Han population

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the Chinese Han population

Variation of Genes Encoding Tryptophan Catabolites Pathway Enzymes in Stroke.

The abnormal activation of the tryptophan catabolites pathway (TRYCATs) is observed in patients suffering from cerebrovascular disease, including stroke. A previous study confirmed that lower bioavailability of tryptophan for serotonin synthesis was characterized in the patients during the acute stroke phase. Interestingly, according to various studies, polymorphisms of the genes involved in the TRYCATs pathway may modulate the risk of stroke occurrence. Therefore, this study aimed to investigate the association between the occurrence of TPH1, TPH2, KAT1, KAT2 and IDO1 polymorphisms and the risk of stroke development.The following 10 polymorphisms of the genes encoding enzymes of the TRYCATs pathway were selected: c.804-7C > A (rs10488682), c.-1668T > A (rs623580), c.803+221C > A (rs1800532), c.-173A > T (rs1799913) – TPH1, c.-1449C > A (rs7963803), and c.-844G > T (rs4570625) – TPH2. c.*456G > A of KAT1 (rs10988134), c.975-7T > C of KAT2 (rs1480544), c.-1849C > A (rs3824259) and c. -1493G > C (rs10089084) of IDO1. The study was carried out on DNA isolated from the peripheral blood taken from 107 patients after a stroke and 107 healthy volunteers. All DNA samples were genotyped using TaqMan probes. The genotypes of eight studied polymorphisms modulated the risk of stroke. No significant difference in genotype and allele frequencies of the c.804-7C > A –TPH1 (rs10488682) and c.*456G > A – KAT1 (rs10988134) polymorphisms were found between patients and controls. Having performed haplotype and gen-gen analyses, it was possible to determine that patients after a stroke and controls differed in terms of the frequency of selected genotypes and haplotypes. Among the studied polymorphisms, eight SNPs were linked with stroke risk modulation. The results obtained confirmed our hypothesis regarding the involvement of the TRYCATs pathway in the pathogenesis of stroke.

The Interaction of TPH2 and 5-HT2A Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study.

Purpose: TPH2 and 5-HT2A appear to play vital roles in the homeostatic regulation of serotonin levels in the brain, their genetic variations may lead to impaired homeostatic regulation of serotonin resulting in abnormal levels of serotonin in the brain, thus predisposing individuals to MDD. However, research studies have yet to confirm which gene-gene interaction effect between TPH2 and 5-HT2A polymorphisms results in increased susceptibility to MDD.Methods: A total of 565 participants, consisting of 278 MDD patients and 287 healthy controls from the Chinese Han population, were recruited for the present study. Six single nucleotide polymorphisms (SNPs) of TPH2/5-HT2A were selected to assess their interaction by use of a generalized multifactor dimensionality reduction method.Results: A-allele carriers of rs11178997 and rs120074175 were more likely to suffer from MDD than T-allele carriers of rs11178997, or G-allele carriers of rs120074175. The interaction between TPH2 (rs120074175, rs11178997) and 5-HT2A (rs7997012) was considered as the best multi-locus model upon the MDD susceptibility.Conclusions: Our data identified an important effect of TPH2 genetic variants (rs11178997 and rs120074175) upon the risk of MDD, and suggested that the interaction of TPH2/5-HT2A polymorphism variants confer a greater susceptibility to MDD in Chinese Han population.

Association study of TPH1 (rs1800532) and TPH2 (rs4570625) Polymorphisms in Type 1 Bipolar Disorder in Iran

Background: Bipolar disorder (BD) has episodes of depression and mania or hypomania. Several studies have been conducted on the role of genes in bipolar disorders and suicidal behaviors, and serotonin-associated genes, Tryptophan hydroxylase (TPH1 and TPH2), are proposed as one of the main effective genetic factors. Methods: In this study, 116 BD patients and 118 age and gender-matched healthy subjects were recruited as the control group. The polymorphisms of THP1 (rs1800532) and TPH2 (rs4570625) genes were identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: There was a positive association of bipolar disorder with CC genotype (P = 0.04) for TPH1 A218C polymorphism, yet not for other genotypes and alleles. There was no association for the genotype and allelic frequency distributions of TPH2-703G/T between bipolar patients and healthy control groups. Conclusions: The TPH1 and TPH2 gene polymorphisms are subjects of many researches. There are contradictions in investigations around the world. These results are in agreement with studies of other populations, yet are different from many studies. There is a need for further investigations.

Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine

Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.

Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety

BackgroundTryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. MethodsWe used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts. ResultsThe TT homozygous males reported less aggressive behaviour in the Life History of Aggression interview at age 25. They also had significantly lower scores in Illinois Bully Scale peer reports, and less ADHD symptoms rated by teachers both at ages 9 and 15. The TT homozygotes of both sexes had the lowest Maladaptive Impulsivity at ages 18 and 25, and the highest Adaptive Impulsivity at age 25. The TT homozygotes also had low depressiveness and trait anxiety by age 25, and the odds ratio for the prevalence of anxiety disorders was 9.38 for the G-allele carriers. LimitationsThe main limitation of the study is the naturally occurring low number of subjects with the TT genotype. ConclusionsSubjects with the TPH2 rs4570625 TT genotype, especially males, exhibit less aggression and a favourable impulsivity profile, and develop anxiety disorders by young adulthood less often.

TPH-2 Polymorphisms Interact with Early Life Stress to Influence Response to Treatment with Antidepressant Drugs.

Background:Variation in genes implicated in monoamine neurotransmission may interact with environmental factors to influence antidepressant response. We aimed to determine how a range of single nucleotide polymorphisms in monoaminergic genes influence this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. An initial study of monoaminergic coding region single nucleotide polymorphisms identified significant associations of TPH2 and HTR1B single nucleotide polymorphisms with treatment response that showed interactions with childhood and recent life stress, respectively (Xu et al., 2012).Methods:A total of 47 further single nucleotide polymorphisms in 17 candidate monoaminergic genes were genotyped in 281 Chinese Han patients with major depressive disorder. Response to 6 weeks’ antidepressant treatment was determined by change in the 17-item Hamilton Depression Rating Scale score, and previous stressful events were evaluated by the Life Events Scale and Childhood Trauma Questionnaire-Short Form.Results:Three TPH2 single nucleotide polymorphisms (rs11178998, rs7963717, and rs2171363) were significantly associated with antidepressant response in this Chinese sample, as was a haplotype in TPH2 (rs2171363 and rs1487278). One of these, rs2171363, showed a significant interaction with childhood adversity in its association with antidepressant response.Conclusions:These findings provide further evidence that variation in TPH2 is associated with antidepressant response and may also interact with childhood trauma to influence outcome of antidepressant treatment.

Interaction of tryptophan hydroxylase 2 gene and life events in susceptibility to major depression in a Chinese Han population

BackgroundMajor depression (MD) results from a complex synergy between genetic and environmental factors. The aim of this study is to analyze the interaction of tryptophan hydroxylase 2 gene (TPH2) variation and negative life events in the pathogenesis of MD. Three TPH2 polymorphisms, −703G/T (rs4570625), −473T/A (rs11178997), and 1463G/A (rs120074175), were selected based on previous findings of associations with MD. MethodsIn this study, 289 patients with MD and 289 age- and sex-matched control subjects were genotyped. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). Gene-environment interactions (G×E) were assessed using the generalized multifactor dimensionality reduction (GMDR) method. ResultsDifferences in rs11178997 and rs120074175 allele frequencies and genotype distributions were observed between MD patients and controls. Significant G×E interactions between negative life events and allelic variation of rs4570625, rs11178997, and rs120074175 were also observed. Individuals carrying the T− genotype of rs4570625 (GG), T− genotype of rs11178997 (AA), or A− genotype of rs120074175 (GG) were susceptible to MD only when exposed to high-negative life events. However, individuals with the T+ genotypes of rs11178997 (TA, TT) and A+ genotypes of rs120074175 (AG, AA) were susceptible to MD when exposed to low-negative life events. LimitationAssessment of negative life events was influenced by subjective interpretation. ConclusionsInteractions between multiple TPH2 gene alleles and negative life events were revealed by GMDR analysis. Chinese Han individuals with at least one rs11178997 T allele or rs120074175 A allele are susceptible to MD even in the relative absence of high-negative life events.

Genetic variability in tryptophan hydroxylase 2 gene in alcohol dependence and alcohol-related psychopathological symptoms

Heritability plays an important role in the development and expression of alcohol dependence. The present genetic association study explored the role of TPH2 polymorphisms and their haplotypes to investigate its role in alcohol dependence and comorbid psychopathological symptoms. The sample included 101 subjects currently diagnosed as alcohol abusers, 100 abstinent alcohol-dependent subjects and 97 healthy controls. Subjects were genotyped for TPH2 rs4570625, rs1843809, rs7305115, rs4290270. TPH2 genotypes were not associated with alcohol dependence, but GGAA haplotype was less common (p=0.038) and GTAA and GGGT were more common (p=0.011 and p=0.021, respectively), in currently dependent patients compared to controls. Exploratory analysis of genotypes in currently dependent patients showed that rs1843809 was associated with depressive and aggressive traits (p=0.045 and p=0.001, respectively), rs4290270 with depressive and anxiety traits (p=0.040 and p=0.025, respectively) and rs4570625 with aggressive traits (p=0.011). In abstinent subjects rs1843809 genotype was associated with traits of social anxiety (p=0.003). Only association between rs1843809 and the BDHI score (p=0.001) and associations between GTAA haplotype and Zung Anxiety Scale and BDHI score (p=0.001 and p<0.001, respectively), in currently dependent patients remained significant after applying the Bonferroni’s correction.Our findings support a potential role of TPH2 in alcohol dependence. TPH2 genetic variability may be also associated with anxiety and aggression traits in alcohol dependent subjects.

Abstract W MP11: Post Stroke Emotional Dysfunction and Fatigue Are Related to Tryptophan Hydroxylase 2 Polymorphsis

Background and Purpose: Emotional dysfunction is a common complication after stroke. Despite reports on serotonergic involvement in the etiology post stroke emotional dysfunction (PSED) and post stroke fatigue (PSF), the role of the TPH1 and TPH2 gene responsible for 5-HT synthesis in PSED and PSF requires analysis. The aim of this study was to investigate the association between different genetic variants of the Tryptophan Hydroxylase (TPH) 1 and TPH2 gene and PSED and PSF at 3 months post- stroke. Method: TPH1 A218C and TPH2 SNPs, rs4641528 and rs10879355 genotyping were performed from genomic DNA which was collected and stored previously from 373 stroke patients. The potential association between TPH1 and TPH2 polymorphisms and post-stroke depression (PSD), post-stroke emotional incontinence (PSEI), and PSF was investigated. Results: PSD, PSEI, and PSF were present in 17.2%, 10.7%, and 44.0% at 3 months post-stroke. Among the patients, 10 (2.7%) had all three PSEDs (PSD, PSEI, and PSF), 37 (9.9%) had two of the three, and 119 (31.9%) had only one among PSD, PSEI, and PSF at 3 months post-stroke.There were no significant differences in the TPH1 A218C genotype or allele frequencies between the patients with PSD, PSEI, or PSF and those without them at 3 months post-stroke. TPH2 SNP rs10879355 was associated with post-stroke fatigue ( p &lt;0.01) at 3 months post-stroke, whereas TPH2 SNP rs4641528 was associated PSD ( p =0.018) and PSEI ( p =0.049). Conclusions: Our results suggested that TPH2 SNPs may have an important effect on PSED and PSF at 3 months post-stroke, but the TPH1 A218C polymorphism plays no significant role in the pathogenesis and clinical symptomatology of PSED and PSF.

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

The tryptophan hydroxylase 2 (Tph2) polymorphism C2432T mediates mRNA expression and responses to antidepressant treatment in a sex‐specific manner

The mechanisms behind successful treatment response in Major Depressive Disorder remain unclear. We examined whether a novel single nucleotide polymorphism (SNP) C2432T in the Tph2 gene mediates differences in response to SSRIs between two mouse strains: MRL/MpJ (MRL; SSRI‐responding, T/T) versus C57Bl/6J (C57; SSRI‐nonresponding, C/C) (Balu et al, 2009). We cross‐bred the MRL and C57 strains to isolate C2432T in the F2 generation and determined functionality using the response to SSRIs in the tail suspension test (TST). F2 T/T females showed an enhanced citalopram response (p&lt;0.001, n=10), while males showed no genotype‐specific effects. The C2432T SNP also mediated Tph2 mRNA expression, with T/T animals showing increased expression in the midbrain (p&lt;0.05, n=11–16). However, in response to chronic SSRI treatment, there was no difference by genotype in F2 generation animals in measures of hippocampal neurogenesis or novelty‐induced hypophagia behavior. The C2432T SNP may mediate serotonin involvement to acute antidepressant response in a sex‐specific manner, but did not mediate the effects of chronic antidepressant treatment.

Association Between TPH2 Gene Polymorphisms and Attention Deficit Hyperactivity Disorder in Korean Children

Attention deficit hyperactivity disorder (ADHD) is a common disorder of the school-age population. ADHD is a familial disorder and genetic studies estimate heritability at 80%-90%. The aim of the present study was to investigate the association between the genetic type and alleles for the TPH2 gene in Korean children with ADHD. The sample consisted of 142 ADHD children and 139 control children. We diagnosed ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 281 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for TPH2 polymorphism. Alleles and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of TPH2 gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the frequencies of the rs11179027 (odd ratio [OR]=2.12, 95% confidence interval [CI]=1.13-3.97, p=0.020) and rs1843809 (OR=0.48, 95% CI=0.24-0.97, p=0.040) of alleles of TPH2, but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggested that TPH2 might be related to ADHD symptoms.

Tryptophan hydroxylase 2 gene polymorphisms and poststroke anxiety disorders

Anxiety is common in stroke survivors and may adversely affect recovery. Polymorphisms of tryptophan hydroxylase2 (THP2) gene have been shown to be associated with anxiety disorders and other affective disorders. This study was aimed to investigate the association of two polymorphisms of THP2 gene, rs4570625 and rs4565946, with poststroke anxiety disorders in a Han Chinese population. This case control study included 112poststroke anxiety patients and 246 non-anxious controls. All participants completed Hamilton Anxiety Rating Scale and DNA was extracted from blood and genotyped for the two polymorphisms of THP2 gene. Results revealed that the G allele of rs4570625 was associated with the increased risk of poststroke anxiety. In the female subgroup, both the GG genotype and G allele were observed to be significantly higher in case than in control. No significant difference in genotype and allele frequencies of the rs4565946 was found between case and control. Haplotype analysis identified that patients with the G-C haplotype had significantly increased the risk of poststroke anxiety. More than 20 TPH2 polymorphisms have been detected, some of which are tightly-linked and may function together, only two SNPs of TPH2 were investigated in this study. The findings suggest that these polymorphisms in TPH2 gene are involved in development of poststroke anxiety in the Han Chinese population.

Association with tryptophan hydroxylase 2 gene polymorphisms and autism spectrum disorders in Korean families

It was performed a family-based association study of 6 single nucleotide polymorphisms (SNPs) from the TPH2 with autism spectrum disorder (ASD) in 151 Korean trios. We found a significant association at the rs2129575 with ASD susceptibility (corrected p=0.006). Furthermore, after conducting with the quantitative scores in the Autism Diagnostic Interview—Revised, there were associations between restricted, repetitive, and stereotyped patterns of behavior (preoccupation with parts of objects or nonfunctional elements of materials) in ASD and SNPs in TPH2. These results suggest that TPH2 polymorphisms influence the phenotypic impairments of ASD and enhance ASD susceptibility.

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg(447) substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [(35)S]GTP-γ-S binding assay and 5-HT(1A) receptor autoradiography, a functional desensitization of 5-HT(1A) autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT(1A) autoreceptors.