Tryptophan Hydroxylase Polymorphism Research Articles

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (VT) using [11C]harmine PET in 51 participants (21 individuals with seasonal affective disorder (SAD) and 30 healthy individuals (HI)). Statistical analyses comprised general linear models with global MAO-A VT as dependent variable, genotype as independent variable and age, sex, group (individuals with SAD, HI) and season as covariates. rs1386494 genotype significantly affected global MAO-A VT after correction for age, group and sex (p < 0.05, corr.), with CC homozygotes showing 26% higher MAO-A levels. The role of rs1386494 on TPH2 function or expression is poorly understood. Our results suggest rs1386494 might have an effect on either, assuming that TPH2 and MAO-A levels are linked by their common product/substrate, 5-HT. Alternatively, rs1386494 might influence MAO-A levels via another mechanism, such as co-inheritance of other genetic variants. Our results provide insight into how genetic variants within serotonin turnover translate to the cerebral serotonin system. Clinicaltrials.gov Identifier: NCT02582398. EUDAMED Number: CIV-AT-13-01-009583.

Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior - a TPH2 imaging genetics approach.

Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance. The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252). Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes. The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.

The relationship of tryptophan hydroxylase-2 methylation to early-life stress and its impact on short-term antidepressant treatment response

IntroductionThe gene tryptophan hydroxylase 2 (TPH2) encodes the associated rate-limiting enzyme in the biosynthesis 5-HT (serotonin). Early life stress and adult variability in TPH2 can correspond with diminished response to antidepressants for patients with major depressive disorder (MDD). DNA methylation is an epigenetic mechanism mediating gene expression, often tempered by environmental factors. Here, we investigate the influence of TPH2 methylation combined with stress on response to antidepressants within the first two weeks of treatment initiation. Methods291 Han Chinese patients with major depressive disorder and 100 healthy controls comprised the study population. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) rated recent and early-life stress. The primary outcome equaled a reduction by ≥ 50% from the Hamilton Depression Rating Scale-17 (HAMD-17) after 2 weeks of treatment. The Illumina HiSeq platform assessed methylation status in 38 CpG sites located upstream and downstream of 11 TPH2 polymorphism sites. ResultsIn 291 patients and 100 healthy controls, 3 CpG sites predict antidepressant treatment response per sex (TPH2-7-142, p=0.012; TPH2-1-43, p=0.033; TPH2-5-203, p=0.036). High-level CTQ scores relate significantly to DNA hypomethylation at CpG-site TPH2-8-237 in males (false discovery rate [FDR]-corrected p=0.038). Additionally, the interaction of hypermethylation in two CpG sites and elevated early-life stress may reduce antidepressant response (TPH2-5-203, FDR corrected p=0.010; TPH2-10-60, FDR corrected p=0.001). ConclusionsOur study suggests that TPH2 methylation and its interaction with early-life stress may impair antidepressant response, suggesting that pharmaco-epigenetic studies could identify epigenetic biomarkers for antidepressant response.

Genetic Variants and Haplotypes of Tryptophan Hydroxylase 2 and Reelin Genes May Be Linked with Attention Deficit Hyperactivity Disorder in Egyptian Children.

Attention-deficit hyperactivity disorder (ADHD) has been proposed to stem from multiple etiologies, perhaps genetic in nature with biological and psychosocial motivates. Tryptophan hydroxylase 2 (TPH2) and Reelin (RELN) genes may play a key role in triggering ADHD. The purpose of this case-controlled study was to explore the linkage of the genetic variants of TPH2 and RELN genes with ADHD. One hundred Egyptian children with ADHD and 105 age and sex matched controls constituted the study samples. Genotyping was performed for TPH2 (rs11179027; rs1843809) and RELN (rs736707; rs362691) gene polymorphisms using real time PCR assay. The alleles and genotype frequencies of TPH2 and RELN gene polymorphisms were assessed in all study participants. The frequencies of the alleles of TPH2 rs11179027 (OR = 1.75, 95% CI = 1.08-2.85, p = 0.022), TPH2 rs1843809 (OR = 3.67, 95% CI = 1.82-7.43, p = <0.001), and RELN rs736707 (OR = 1.61, 95% CI = 1.03-2.51, p = 0.035) were significantly associated with ADHD, while there was no significant difference between ADHD patients and controls regarding the frequency of RELN rs362691 (OR = 1.34, 95% CI = 0.73-2.48, p = 0.34). The frequencies of CTAG, CTGG, CTAC, CTGC, and GTAC haplotypes were significantly higher in ADHD patients than in controls (p = 0.011, 0.005, 0.015, 0.001, and 0.027, respectively). In conclusion, TPH2 rs11179027, TPH2 rs1843809, and RELN rs736707 gene alleles and haplotypes might be significantly correlated with the genetic susceptibility to ADHD in Egyptian children.

Tryptophan hydroxylase-2 polymorphism is associated with white matter integrity in first-episode, medication-naïve major depressive disorder patients

Considerable evidence suggests that the tryptophan hydroxylase-2 (TPH2) gene is associated with the pathophysiology of major depressive disorder (MDD). In the present study, we investigated alterations of white matter (WM) integrity and the impact of TPH2 polymorphism on WM in a sample of 118 first-episode, medication-naïve, MDD patients and 118 well-matched healthy controls. Whole brain analyses of fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). The results showed that the MDD group had significantly reduced FA values for the genu and body of the corpus callosum (CC) and the bilateral anterior corona radiate (ACR). In the MDD patient group, the GG homozygote subgroup exhibited a widespread reduction of FA (uncorrected) and significantly reduced FA in the left retrolenticular portion of the internal capsule and left superior longitudinal fasciculus (SLF) compared with those of the T carriers (GT/TT) (FWE corrected). No significant correlation was found between the FA values in any brain region and the patients' clinical variables. Our findings demonstrate the presence of abnormal white matter integrity in untreated patients with first-episode depression. TPH2-rs4570625 polymorphisms may be involved in the pathological mechanism of WM microarchitecture in patients.

Association of Fatigue With TPH2 Genetic Polymorphisms in Women With Irritable Bowel Syndrome.

Fatigue is the most common extraintestinal symptom in women with irritable bowel syndrome (IBS). Genetic polymorphisms of monoamines are associated with fatigue in many chronic diseases. In this pilot exploratory study, the primary aim was to determine whether genetic polymorphisms of tryptophan hydroxylase ( TPH1/TPH2), serotonin reuptake transporter ( SERT), or catechol-O-methyltransferase ( COMT) are associated with fatigue in women with IBS. Additionally, analysis explored whether these genetic associations with fatigue would be present when controlling for abdominal pain, psychological distress, feeling stressed, and sleepiness during the day. Secondary analysis of two randomized controlled trial baseline data sets in Caucasian women with IBS ( N = 185) was conducted. Participants kept a daily diary with one dimension (i.e., severity) for each of the 26 symptoms, including fatigue, for 28 days prior to randomization. DNA samples were tested for single-nucleotide polymorphisms (SNPs) of TPH1 (four SNPs) /TPH2 (one SNP), SERT (one SNP), and COMT (one SNP). Analysis of covariance was used to examine associations of percentage of diary days with moderate to very severe symptoms with genetic polymorphisms. Only one SNP, TPH2 rs4570625, was significantly associated with fatigue ( p = .005). T-allele (low functional) carriers of TPH2 (i.e., G/T or T/T genotypes) reported a greater percentage of days with moderate to very severe fatigue than G/G homozygotes ( p = .001). Reduced synthesis of tryptophan in the central nervous system may contribute to reports of fatigue in women with IBS. Understanding genetic risk factors for fatigue may elucidate preemptive strategies to reduce fatigue in individuals with IBS.

Association study of interaction of tryptophan hydroxylase 2 with serotonin 1A receptor gene polymorphism on major depressive disorder

Objective To explore the interaction between tryptophan hydroxylase 2(TPH2) gene polymorphisms (rs4570625, rs11178997) and serotonin 1A receptor(5-HT1A) gene polymorphisms (rs878567, rs1364043, rs6265) and the association with major depressive disorder (MDD) in a Chinese Han population. Methods The DNA isolated from peripheral blood samples of 288 MDD patients 288 healthy subjects was detected by single base primer extension assay (Snapshot). The generalized multifactor dimensionality reduction (GMDR) method was used to analyze the gene-gene interaction. Results Significant differences were found in the genotype(patients (TT: 27, TA: 152, AA: 109), controls (TT: 82, TA: 105, AA: 101), P<0.01) and allele(patients (T: 206, A: 370), controls (T: 269, A: 307), P<0.01) frequencies of rs11178997 within TPH2 between MDD patients and controls. Statistically, a greater risk of developing MDD was found in individuals with an rs11178997 A-allele(OR=1.574, 95%CI=1.243-1.993). The interaction between TPH2 (rs4570625, rs11178997) and 5-HT1A (rs878567, rs1364043, rs6265) was considered as the best multi-locus model, and this showed a testing accuracy of 57.67% and a CV consistency of 10/10. And this interaction had a significant effect on the risk of MDD (P=0.0107). Conclusion There may be an association between the interaction of TPH2 and 5-HT1A polymorphisms and MDD. Key words: Major depressive disorder; Tryptophan hydroxylase 2; Serotonin 1A receptor; Gene-gene interaction

Association of tryptophan hydroxylase-2 polymorphisms with oppositional defiant disorder in a Chinese Han population.

BackgroundOppositional defiant disorder (ODD) is a behavioral disorder of school-age population. It is well known that 5-HT dysfunction is correlated with impulsivity, which is one of the common characteristics of ODD. The enzyme tryptophan hydroxylase-2 (TPH-2) synthesizes 5-HT in serotonergic neurons of the midbrain raphe. The purposes of this study were to investigate the potential association of TPH-2 polymorphisms with susceptibility to ODD in a Han Chinese school population.MethodsFour polymorphisms (rs4570625, rs11178997, rs1386494 and rs7305115) of the TPH-2 gene were analyzed by using polymerase chain reaction and DNA microarray hybridization in a case–control study of 276 Han Chinese individuals (124 ODD and 152 controls).ResultsIn single marker analyses,there was a significant difference in the genotype (χ 2 = 4.163, P = 0.041) and allele frequency (χ 2 = 3.930, P = 0.047) of rs1386494 between ODD and control groups. Haplotype analyses revealed higher frequencies of haplotypes TA (rs4570625-rs11178997), TAG (rs4570625-rs11178997-rs1386494), TAA (rs4570625-rs11178997-rs7305115) and TAGA (rs4570625-rs11178997-rs1386494-rs7305115), but lower frequencies of haplotypes GA (rs4570625-rs11178997) and GAG (rs4570625-rs11178997-rs1386494) in ODD compared to control groups.ConclusionsThese findings suggest the role of these TPH-2 gene variants in susceptibility to ODD. Some haplotypes might be the risk factors for Chinese Han children with ODD, while others might be preventable factors.

A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val66Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects.

Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as ‘risk’ genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF—Met allele (including Met/Val and Met/Met) when combined with the TPH2—T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common psychiatric disorders and should be targets for future clinical investigation.

Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity.

Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine that has various functions in both neuronal and non-neuronal systems. In the central nervous system, 5-HT regulates mood and feeding behaviors as a neurotransmitter. Thus, there have been many trials aimed at increasing the activity of 5-HT in the central nervous system, and some of the developed methods are already used in the clinical setting as anti-obesity drugs. Unfortunately, some drugs were withdrawn due to the development of unwanted peripheral side effects, such as valvular heart disease and pulmonary hypertension. Recent studies revealed that peripheral 5-HT plays an important role in metabolic regulation in peripheral tissues, where it suppresses adaptive thermogenesis in brown adipose tissue. Inhibition of 5-HT synthesis reduced the weight gain and improved the metabolic dysfunction in a diet-induced obesity mouse model. Genome-wide association studies also revealed genetic associations between the serotonergic system and obesity. Several genetic polymorphisms in tryptophan hydroxylase and 5-HT receptors were shown to have strong associations with obesity. These results support the clinical significance of the peripheral serotonergic system as a therapeutic target for obesity and diabetes.

Association between the TPH1 A218C polymorphism and antidepressant response: evidence from an updated ethnicity, antidepressant-specific, and ethnicity-antidepressant interaction meta-analysis.

Several studies have investigated the potential association between genetic polymorphisms of tryptophan hydroxylase 1 (TPH1) and antidepressant response. However, the results are inconsistent and inconclusive. Our aim was to assess the association of the TPH1 A218C polymorphism (rs1800532) with antidepressant response using ethnicity, antidepressant-specific, and ethnicity-antidepressant interactions in an updated meta-analysis. Data were collected from the related literature published before December 2013 from MEDLINE and EMBASE databases. The meta-analysis was stratified by ethnicity, antidepressants, and ethnicity-antidepressant interaction, and was carried out using a random-effects model as appropriate using the Stata Statistical Package (version 11.0). A total of 12 individual studies and the STAR*D study were identified in the current study, among which six studies and the STAR*D study (White part) reported on the TPH1 A218C polymorphism and antidepressant response in a White population, with 2035 cases, and six studies and the STAR*D study (Asian part) were carried out in an Asian population, with 707 cases. In terms of the classes of antidepressants, eight studies and the STAR*D study explored this relationship using selective serotonin reuptake inhibitors (SSRIs) and four studies used other/mixed antidepressants. We found that the TPH1 A218C genotype was not significantly associated with antidepressant response either in all populations or in White and Asian populations. Moreover, the results did not change according to an ethnicity-antidepressant interaction model either in White populations using SSRIs or other/mixed antidepressants or in Asian populations. The TPH1 A218C polymorphism may not be associated with antidepressant response either in an ethnicity, antidepressant-specific population or in an ethnicity-antidepressant interaction model.

Tryptophan hydroxylase 2 (TPH2) gene polymorphisms and psychiatric comorbidities in temporal lobe epilepsy

Psychiatric comorbidities are frequent in temporal lobe epilepsy (TLE). It is plausible that variance in serotonin-related genes is involved in the susceptibility of these associations. We report here the results on the association of tryptophan hydroxylase 2 (TPH2) gene polymorphisms with psychiatric comorbidities in TLE. A cohort study was conducted on 163 patients with TLE. We assessed the influence of the rs4570625 and rs17110747 polymorphisms in the TPH2 gene on psychiatric comorbidities in TLE. In patients with TLE, the presence of the T allele in the rs4570625 polymorphism was associated with psychotic disorders (OR=6.28; 95% CI=1.27–17.54; p=0.02), while the presence of the A allele in the rs17110747 polymorphism was associated with alcohol abuse (OR=20.33; 95% CI=1.60–258.46; p=0.02). Moreover, we identified male gender (OR=11.24; 95% CI=1.68–76.92; p=0.01) and family history of psychiatric disorder (OR=15.87; 95% CI=2.46–100; p=0.004) as factors also associated with alcohol abuse in TLE. Conversely, a family history of epilepsy was inversely associated with alcohol abuse (OR=0.03; 95% CI=0.001–0.60; p=0.02). Tryptophan hydroxylase 2 gene allele variants might be risk factors for psychiatric conditions in TLE. More specifically, we observed that the T allele in the rs4570625 polymorphism was associated with psychotic disorders, and the A allele in the rs17110747 TPH2 polymorphism was associated with alcohol abuse in patients with TLE. We believe that this study may open new research venues on the influence of the serotonergic system associated with psychiatric comorbidities in epilepsy.

EPA-1746 – The role of family structure and of tryptophan hydroxylase 2 (TPH2) on the stability of deficient emotional self-regulation symptoms throughout adolescence

Deficient emotional self-regulation (DESR) have been found to be a very heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behaviour. A common single nucleotide polymorphism (SNP G-703T, rs 4570625) in the transcriptional control region of TPH2 has been reported to modulate amygdala responsiveness to affective stimuli and has been found to be associated with emotional dysregulation. we have investigated the moderating role of a TPH2 polymorphism on genesis and stability/instability of DESR during the transition from early to late adolescence, taking also into account the possible interaction with family structure. This is a five year follow-up study of the genetic section of the PrISMA project (Progetto Italiano Salute Mentale Adolescenti) The final study population included 287 subjects (50.9% boys, 49.1% girls, aged 15-19). To test for hypothesized influences and moderation effect of TPH2 genotype we performed a path analysis using Mplus 6.11 and the bootstrapping procedure describe by Preacher et al. (2007) The effect of family structure on early-adolescence DESR is moderated by TPH2 genotype: subjects living in monoparental families which are also homozygous for G-allele show higher scores on DESR index. Otherwise, the effect of family structure on late-adolescence DESR is mediated by the same symptoms in early-adolescence and this mediation is moderated by TPH2 G-703T polymorphism Future models of the developmental link between environmental adversities and dysregulation problems therefore need to consider that a more ‘dynamic’ G×E perspective.

Lack of association between TPH2 gene polymorphisms with major depressive disorder in multiethnic Malaysian population

Numerous association studies of candidate genes studies with major depressive disorder (MDD) have been conducted for many years; however, the evidence of association between genes and the risk of developing MDD still remains inconclusive. In this study, we aimed to investigate the association between the tryptophan hydroxylase 2 (TPH2) gene and MDD in three ethnic groups (Malay, Chinese and Indian) within the Malaysian population. Two hundred and sixty five MDD patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for MDD and 332 healthy controls were recruited for the study. All cases and controls were then genotyped for TPH2 polymorphisms rs1386494, rs1386495 and rs7305115. Single locus analysis in pooled and ethnically stratified subjects revealed no association between each of the three variants of the TPH2 gene with susceptibility to MDD. Strong linkage disequilibrium was detected between rs1386495 and rs1386494 in pooled subjects; however, no significant association was found in the haplotype analysis. In this study, we suggest that in both the Chinese and Indian populations, gender distribution differ significantly between cases and controls, showing that women are more at risk of developing MDD compared with men. Therefore, we suggest that the occurrence of MDD in both Chinese and Indians in the Malaysian population may be influenced by gender.

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.

Emotion appraisal and the tryptophan hydroxylase 2 (TPH2) gene

The purpose of this study was to investigate the association between the G-703T polymorphism of the tryptophan hydroxylase 2 (TPH2) gene (rs4570625) and emotion appraisal in healthy volunteers. Participants were asked to recall a situation characterized by a strong emotion and to rate appraisal processes: novelty/expectation, pleasantness, goal-conduciveness, fairness, responsibility/causation, coping ability, morality, and relationship to self-concept. Results revealed that in the case of fear- and sadness-related autobiographical memories, participants with the GG genotype achieved higher appraisal scores for goal-conduciveness and lower scores for coping ability compared with participants with the TT genotype. In the case of joy, no differences were observed across genotypes. These results suggest that the TPH2 polymorphism affects appraisal processes in the case of negative emotions.

Association between the TPH1 A218C polymorphism and risk of mood disorders and alcohol dependence: Evidence from the current studies

Several studies have assessed the association between genetic polymorphisms of tryptophan hydroxylase (TPH1) and risk of mood disorders and alcohol dependence, with controversial results. Our aim was to assess the association of TPH1 A218C polymorphism (rs1800532) with mood disorders, including major depressive disorder and bipolar disorder, and alcohol dependence by using meta-analysis. Data were collected from the related literatures published until November 25, 2010 from MEDLINE, EMBASE and ISI Web of Science databases, and meta-analysis stratified by ethnicity was performed in either fixed or random effect model as appropriate by using Stata Statistical Package (version 10.0). Twenty-seven individual studies were included in the current study, among which, there were 9 studies for bipolar disorder, with 1951 cases and 2161 controls, 14 studies for major depressive disorder, with 2340 cases and 3204 controls, and 4 studies for alcohol dependence, with 601 cases and 711 controls. We found that in Caucasian population, the TPH1 218AA genotype was significantly associated with increased bipolar disorder risk (recessive comparison: OR, 1.42; Bonferroni-adjusted P=0.006; homozygote comparison: OR, 1.63; Bonferroni-adjusted P=0.072), and elevated alcohol dependence risk (recessive comparison: OR, 1.83; Bonferroni-adjusted P=0.012), while the association was not significant in Asian population. Moreover, the A218C polymorphism did not appear to have any effect on major depressive disorder risk either in Caucasians or in Asians. The TPH1 A218C polymorphism is a potential biomarker for bipolar disorder and alcohol dependence risk in Caucasian population.

TPH2 G/T polymorphism is associated with hyperphagia, IQ, and internalizing problems in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by intellectual disabilities, growth hormone dysregulation, hyperphagia, increased risks of morbid obesity, compulsive behaviors, and irritability. As aberrant serotonergic functioning is strongly implicated in PWS, we examined associations between the PWS phenotype and polymorphisms in tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of serotonin in the brain. Ninety-two individuals with PWS aged 4 to 50 years (M = 21.97) were genotyped for the TPH2 G703-T polymorphism. IQ testing was conducted in offspring, and parents completed questionnaires that tapped their child's compulsivity, hyperphagia, and other behavior problems. As expected, the frequency of G/T or T/T polymorphisms in participants with PWS (39%) was similar to rates found in the general population (38%). Compared to those with a homozygous (G/G) genotype, individuals with a T allele had significantly higher hyperphagic behavior, drive, and severity scores, and they also had a younger age of onset of hyperphagia. Those with a T allele also had higher IQ scores than their counterparts. Females with a T allele had significantly higher internalizing symptoms, primarily anxiety and depression, than all others. TPH2 G/T polymorphisms, and presumed loss of enzyme function, were associated with specific aspects of the PWS phenotype. Aberrant serotonergic functioning is strongly implicated in hyperphagia in PWS, and females with TPH2 T alleles may be at higher risk for affective or mood disorders. Findings hold promise for examining other serotonin-altering genes in PWS, and for future serotonin-altering treatment trials.

P02-225 - TPH2 Polymorphisms and alcohol-related suicide

IntroductionSubstantial evidence from family, twin, and adoption studies corroborates implication of genetic and environmental factors, as well as their interactions, on suicidal behavior and alcoholism risk. Serotonergic disfunction seems to be involved in the pathophysiology of substance abuse, and has also an important role in suicidal behavior.ObjectivesRecent studies of the tryptophan hydroxylase 2 (TPH2) showed mild or no association with suicide and alcohol-related suicide.AimsInvestigation of the role of five single nucleotide polymorphisms (SNPs), one functional (p.Arg441His), two in intron 5 (Rs1843809, Rs1386493), and two in the 5’ regulatory promoter region (Rs4131348, Rs11178997) of TPH2, in association with suicide and alcohol-related suicide on a population with one of the highest suicide rates in the world.MethodsWe performed qRT-PCR (Real-Time Polymerase Chain Reaction) genotyping analysis of SNPs and alcohol analysis on 388 suicide victims and 227 controls.ResultsThe results showed association between suicide (P(X2) = 0.043) and alcohol-related suicide (P(X2) = 0.021) for SNP Rs1843809. A tendency for association was determined also for polymorphism Rs1386493 (P(X2) = 0.055) and alcohol-related suicide. Data acquired from psychological autopsies in a subsample of suicide victims (n = 79) determined more impulsive behavior (P(X2) = 0.016) and verbal aggressive behavior (P(X2) = 0.025) in the subgroup with alcohol misuse or dependency.ConclusionsOur results suggest implication of polymorphisms in suicide and alcohol-related suicide, but further studies are needed to clarify the interplay among serotonergic system disfunction, suicide, alcohol dependence, impulsivity and the role of TPH2 enzyme.

Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: A perspective

Based on genetic variation, there is accumulating evidence that altered function of tryptophan hydroxylase-2 (TPH2), the enzyme critical for synthesis of serotonin (5-HT) in the brain, plays a role in anxiety-, aggression- and depression-related personality traits and in the pathogenesis of disorders featuring deficits in cognitive control and emotion regulation. Here, we appraise the genetic and neurobiological evidence to illustrate the critical role of TPH2 in central 5-HT system function and in the pathophysiology of a wide spectrum of disorders of cognitive control and emotion regulation, ranging from depression to attention-deficit/hyperactivity disorder (ADHD), a phenotype commonly associated with difficulties in the control of emotion and with a high co-morbidity of depression. Findings from psychophysiological and functional imaging studies are indicative of various TPH2 polymorphisms directly influencing serotonergic function and thus impacting on mood disorders and on the response to antidepressant treatment. Especially a combination with uncontrollable stress seems to potentiate these effects linking gene-environment interaction directly with behavioral dysfunction in human and animal models. TPH2-deficient mice display alterations in anxiety-like behavior which is accompanied by adaptational changes of 5-HT(1A) receptors and its associated signaling pathway. Mouse models in conjunction with cognitive neuroscience approaches in humans are providing unexpected results and it may well be that future research on TPH2 will provide an entirely new view of 5-HT in brain development and function related to neuropsychiatric disorders.