Family-based association study of TPH1 and TPH2 polymorphisms in autism.

The TPH1 and TPH2 genes encode the rate-limiting enzymes that control serotonin biosynthesis, and serotonin is clearly altered in autism. In the current study, eight SNPs in the TPH1 gene region and eight SNPs within the TPH2 gene were examined by family-based association tests in a large cohort of 352 families with autism and in clinically defined subsets of these families with either severe obsessive-compulsive behaviors (sOCB) or self-stimulatory behaviors (SSB). We found no evidence for association between autism and single SNPs or haplotypes of the TPH1 and TPH2 genes in the cohort of all families or in the sOCB and SSB subsets. In particular, we failed to replicate the association between autism and variants of the TPH2 gene, rs4341581 (TRANSMIT P = 1; PDT P = 0.323; FBAT P = 0.446) and rs11179000 (TRANSMIT P = 0.174; PDT P = 0.293; FBAT P = 0.374). Furthermore, no evidence for linkage was observed between autism and SNPs in the TPH1 and TPH2 genes (although linkage at the TPH2 locus was observed in the SSB subset). Thus, it appears unlikely that the TPH1 and TPH2 genes play a significant role in the susceptibility to autism or to autism endophenotypes including sOCB and SSB.     

TPH2 polymorphisms and alcohol-related suicide

Substantial 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. Recent studies of the tryptophan hydroxylase 2 showed mild or no association with suicide and alcohol-related suicide. We performed SNP and alcohol analysis on 388 suicide victims and 227 controls. The results showed association between suicide (Pχ2=0.043) and alcohol-related suicide (Pχ2=0.021) for SNP Rs1843809. A tendency for association was determined also for polymorphism Rs1386493 (Pχ2=0.055) and alcohol-related suicide. Data acquired from psychological autopsies in a subsample of suicide victims (n=79) determined more impulsive behavior (Pχ2=0.016) and verbal aggressive behavior (Pχ2=0.025) in the subgroup with alcohol misuse or dependency. In conclusion, our 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.     

大鼠多重脑震荡后脑内TPH表达变化

目的:探讨多重脑震荡(multiple cerebral concussion,MCC)后脑内5-HT能神经元内色氨酸羟化酶(tryptophan hydroxylase,TPH)含量的变化。方法:42只雄性大鼠随即分为7组,每组6只,一组为对照组,其余的大鼠用金属单摆式机械打击装置复制MCC大鼠模型,伤后分1~24 d不同时段的6个损伤组,用免疫组化技术和图像分析方法观察基底前脑及脑干5-HT能神经元内TPH含量的变化。结果:多重脑震荡后2~8 d上述脑区TPH免疫阳性表达升高(P<0.05),伤后24 d趋于正常(P>0.05)。结论:多重脑震荡后5-HT神经元TPH表达增强,可能与脑损伤后神经元的应激反应有关。     

TPH基因-G1066A位点遗传多态性与抑郁症相关性的研究

目的调查色氨酸羟化酶基因-G1066A位点的遗传多态性在中国北方抑郁症群体中的分布。方法采用聚合酶链反应-限制性片段长度多态性分析方法,检测140名对照个体和73名抑郁症患者的TPH基因-G1066A位点。结果TPH基因-G1066A位点在对照组中其等位基因A的频率为0.186,G为0.814;抑郁症患者中等位基因A频率为0.205,G为0.795。结论TPH基因-G1066A位点等位基因A在中国北方抑郁症群体中有较高频率的分布,提示等位基因A可能是抑郁症的易感基因。     

Decoding whole genome of Anoxybacillus rupiensis TPH1 isolated from tatapani hot spring,India and giving insight into bioremediation ability of TPH1 via heavy metals and azo dyes

A moderately thermophilic, gram-positive genomospecies Anoxybacillus rupiensis TPH1 was isolated from Tatapani hot spring, Chhattisgarh, India. Genome of 3.70 Mb with 42.3% GC subsumed 4131 CDSs, 65 tRNA, 5 rRNA, 35 AMR and 19 drug target genes. Further, comparative genomics of 19 Anoxybacillus spp. exhibited an open pan genome of 13102 genes along with core (10.62%), unique (43.5%) and accessory (45.9%) genes. Moreover, phylogenomic tree displayed clustering of Anoxybacillus spp. into two distinct clades where clade A species harbored larger genomes, more unique genes, CDS and hypothetical proteins than clade B species. Further, distribution of azoreductases showed FMN-binding NADPH azoreductase (AzoRed1) presence in clade A species only and FMN-binding NADH azoreductase (AzoRed2) harboring by species of both clades. Heavy metal resistance genes distribution showed omnipresence of znuA, copZ and arsC in both clades, dispersed presence of cbiM, czcD, merA and feoB over both clades and harboring of nikA and acr3 by few species of clade A only. Additionally, molecular docking of AzoRed1, AzoRed2, ZnuA, CopZ, Acr3, CbiM, CzcD, MerA and NikA with their respective ligands indicated high affinity and stable binding. Conclusively, present study provided insight into gene repertoire of genus Anoxybacillus and a basis for the potential application of this thermophile in bioremediation of azo dyes and heavy metals.     

Association of TPH1 with suicidal behaviour and psychiatric disorders in the Chinese population

Tryptophan hydroxylase (TPH), the rate limiting enzyme in serotonin biosynthesis, is one of the most important regulating factors in the serotonergic system. Recently, polymorphisms of the TPH gene have been identified as being associated with suicide, but the evidence is inconsistent. To investigate the role in suicide of one of the isoforms, TPH1, we examined the association of five single nucleotide polymorphisms (SNPs) in the promoter region and in intron 7 of the TPH1 gene based on a sample from the Chinese population of 810 subjects, of whom 329 had made no suicide attempts (NSA), 297 had made suicide attempts (SA), and 184 were healthy subjects (HS). In this study, we observed statistically significant differences between NSA and HS subjects in allele distributions on one marker, −6526A (p=0.0329; odds ratio (OR) 1.36; 95% confidence interval (CI) 1.01 to 1.81). No significant difference in genotype distribution or allele frequencies of other polymorphisms was found between the suicide victims and the controls. The overall haplotype frequency was significantly different between cases and healthy controls (p=0.000024 NSA v HS; p<0.000001, SA v HS; p<0.000001, cases v HS). We found the haplotype TCAAA of −7180/−7065/−6526/218/779 to be strongly associated with suicidal behaviour and psychiatric disorders (p=0.00243; OR=1.62; 95% CI 1.17 to 2.24 and p=0.018; OR=1.41; 95% CI 1.05 to 1.91), which suggests an association of TPH1 with suicidal behaviour and indicates that TPH1 may play a significant role in the aetiology of psychiatric disorders in the Han Chinese population.     

色氨酸羟化酶2在去卵巢抑郁症模型大鼠中缝核中表达减少

目的 观察去卵巢抑郁症大鼠模型海马5-羟色胺(5-HT)含量及其合成限速酶-色氨酸羟化酶2(TPH2)表达的变化.方法 雌性SD大鼠,在卵巢切除术的基础上,联合孤养和21 d慢性不可预见性温和刺激(CUMS)制备去卵巢抑郁症大鼠模型,以行为学测试进行评价.用高效液相色谱-电化学法((HPLC-ECD)测定海马5-HT含量;用RT-PCR技术检测中缝核TPH2 mRNA表达量;用荧光免疫组化检测中缝核TPH2蛋白表达.结果 21 d应激后,模型组大鼠直立活动得分及水平活动得分均减少,糖水消耗百分比下降;海马5-HT含量下降;中缝核TPH2 mRNA表达量及TPH2阳性神经元数量减少.结论 在卵巢切除术的基础上,联合孤养和21 d CUMS可造成去卵巢抑郁症大鼠模型;模型大鼠海马5-HT含量下降,可能是中缝核TPH2的表达减少所致.     

A common TPH2 haplotype regulates the neural processing of a cognitive control demand

The monoamine neurotransmitter, serotonin, critically regulates the function of the cerebral cortex and is involved in psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin with the neuron-specific TPH2 isoform present exclusively in the brain and encoded by the TPH2 gene on chromosome 12q21. The haplotype structure of TPH2 was defined for 16 single-nucleotide polymorphisms (SNPs) in a healthy subject population and a haplotype block analysis confirmed the presence of a six SNP haplotype in a yin configuration that has previously been associated with risk for suicidality, depression, and anxiety disorders. Functional magnetic resonance imaging (fMRI) was used to assess the influence of TPH2 variation on brain function related to cognitive control using the Multi-Source Interference Task (MSIT). The MSIT-related blood oxygen level-dependent (BOLD) response was increased with increasing copies of the TPH2 yin haplotype for the dorsal anterior cingulate cortex (dACC), right inferior frontal cortex (IFC), and anterior striatum. A functional connectivity analysis further revealed that increasing numbers of the TPH2 yin haplotype was associated with diminished functional coupling between the dACC and the right IFC, precentral gyrus, parietal cortex and dlPFC. A moderation analysis indicated that the relationship between neural processing networks and cognitive control was significantly modulated by allelic variation for the TPH2 yin haplotype. These findings suggest that the association of risk for psychiatric disorders with a common TPH2 yin haplotype is related to the inefficient functional engagement of cortical areas involved in cognitive control and alterations in the mode of functional connectivity of dACC pathways. ? 2012 Wiley Periodicals, Inc.     

No association between TPH2 gene polymorphisms and ADHD in a UK sample

Tryptophan Hydroxylase 2 (TPH2) is the rate-limiting enzyme in the biosynthesis of serotonin which is exclusively expressed in the brain. Recent molecular studies reported significant association between markers mapped to TPH2 and psychiatric conditions including ADHD. We have examined four single nucleotide polymorphisms (SNPs) two of which (rs1843809, rs1386493) were reported to associate with ADHD in an Irish ADHD sample. Transmission disequilibrium analysis revealed no significant association between any of these markers and ADHD. Dividing by the sex of the transmitting parent has also failed to replicate the previously reported paternal over-transmission of the associated alleles to ADHD probands. A larger sample size will be required to clarify if TPH2 alleles are or are not associated with ADHD.     

Pleiotropic effect of the TPH A779C polymorphism on nicotine dependence and personality.

Recent studies from molecular genetics have suggested an association between the tryptophan hydroxylase 1 (TPH1) gene and nicotine addiction indicating a dysfunction of the serotonergic (5-HT) system in smoking behavior. In a sample of 252 healthy subjects, a significant association between variations observed in nicotine dependence and the heterozygous AC-genotype of the TPH A779C polymorphism could be demonstrated. Moreover, the heterozygous genotype was significantly associated with a personality trait of neurotic aggression (indirect hostility, negativism), as measured by the Buss-Durkee-Hostility-Inventory (BDHI). The positive heterosis effects with respect to nicotine addiction and personality support the idea that the TPH1 gene exerts pleiotropic effects.     

Identification of genetic variants in the neuronal form of tryptophan hydroxylase (TPH2)

OBJECTIVE: We screened the complete protein coding sequence of the newly identified neuronal form of tryptophan hydroxylase (TPH2) for genetic variants. METHODS: Genomic DNA samples from 24 African-Americans and 24 Caucasian-Americans in the Coriell human variation collection were screened by denaturing high-performance liquid chromatography followed by sequencing. RESULTS: We identified a number of genetic variants in both the coding and exon-flanking intronic sequences. Only one variant was identified that predicts a structural change in the TPH2 protein, and this was seen in only one out of 96 chromosomes. CONCLUSIONS: The gene for TPH2 contains a number of polymorphisms that might serve as useful markers for association analyses of complex behavioral phenotypes or as actual risk factors. Structural polymorphisms are extremely rare in TPH2 and cannot therefore act as substantial risk factors for behavioral disorders in African-American and Caucasian populations.     

Tryptophan hydroxylase gene (TPH1) and peripheral tryptophan levels in depression

BACKGROUND: Genetic variants have been discovered in two genes encoding for tryptophan hydroxylase (TPH)-TPH1 and TPH2. Low tryptophan (TRP) levels are associated with depression and may arise because of stress. Evidence suggests that hypothalamic and peripheral 5HT systems have a significant role in appetite regulation, possibly a homeostatic mechanism in regulating peripheral TRP levels. METHODS: We examined the association between a polymorphism in intron 7 of TPH1, 218A>C and plasma total TRP levels in 118 patients with major depression. RESULTS: There was an interaction between 218A>C and gender in determining plasma TRP whereby presence of the 218C allele, in women, was associated with markedly reduced plasma TRP. LIMITATIONS: The study investigated only the TRP1 gene and did not use a haplotype analysis. The results only apply to a population of subjects suffering from major depression. CONCLUSIONS: TPH1 may be associated with the regulation of peripheral tryptophan levels and therefore availability of tryptophan to the brain. This may have relevance to a range of neuropsychiatric conditions.     

Genetic Variation at the TPH2 Gene Influences Impulsivity in Addition to Eating Disorders

Genes are involved in eating disorders (EDs) and self-induced vomiting (SV), a key symptom of different types of EDs. Perfectionism and impulsivity are potential risk factors for EDs. TPH2 (tryptophan hydroxylase 2) SNP rs1473473 was previously associated with anorexia nervosa and EDs characterized by SV. Could perfectionism or impulsivity be underlying the association between rs1473473 and EDs? Genetic association between TPH2 SNP rs1473473 and perfectionism or impulsivity was first evaluated in a random control group (N = 512). The associations obtained in this control group were subsequently tested in a group of patients with an ED (N = 267). The minor allele of rs1473473 (OR = 1.49) was more frequent in impulsive controls, but also in impulsive patients with an ED (OR = 1.83). The largest effect was found in the patients with an ED characterized by SV (OR = 2.51, p = 0.02). Genetic variation at the TPH2 gene appeared to affect impulsivity which, in turn, might predispose to the SV phenotype.     

No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. TPH2 is a recently discovered isoform that is expressed predominantly in serotonin neurons. Associations are reported of TPH2 polymorphisms with MDD, bipolar disorder and suicidal behavior. This study examines a single nucleotide polymorphism in the putative promoter region of the TPH2 gene. METHODS: One hundred nine bipolar, 324 major depressive disorder, and 130 healthy volunteers were genotyped for the rs4131347 (-C8347G) promoter SNP. Association was assessed with diagnosis, suicide attempt status, severity of psychopathology and cerebrospinal fluid monoamine metabolite levels of 5-HIAA, HVA, and MHPG. General linear models and logistic regression tested the effect of genotype*childhood abuse interactions on psychopathology severity and suicide attempt. RESULTS: There was no association between genotype and either mood disorder, suicide attempt status, psychopathology severity or CSF monoamine metabolite levels. CONCLUSIONS: No association was detected between the rs4131347 (-C8347G) SNP in the promoter region of the TPH2 gene and mood disorders, suicidal behavior or monoamine function.     

产时胎儿头皮组织PH值测定用螺旋式合金型PH传感器的研制

产时胎儿窘迫可因多种原因引起，其诊断常以胎儿有无因缺氧引起的酸中毒为依据。国外对此早有研究，并提出以玻璃微电极插入胎儿头皮组织，以检测胎儿头皮组织的ＰＨ值作为诊断依据。只是由于玻璃微电极易破损，不安全且由于检测装置庞大，操作复杂因而未能及早推广。我们研制的螺旋式合金型ＰＨ传感器由合金型ＰＨ敏感电极及准固态参比电极构成。经临床５２例产时胎儿头皮组织ＰＨ值检测证实，其结构科学，检测方法简便、安全，可作连续监测，为胎儿窘迫的诊断提供一种新途径。     

新疆维吾尔族群体色氨酸羟化酶1基因T3804A位点多态性与抑郁症的关联

目的探讨新疆维吾尔族群体色氨酸羟化酶1(TPH1)基因T3804A(rs623580)位点多态性与抑郁症的关系。方法采用聚合酶链式反应产物直接测序的方法检测104例抑郁症患者(研究组)和90例正常体检者(对照组)TPH1基因rs623580位点的基因型。应用SPSS10.0分析基因多态性与抑郁症相关性。结果研究组与对照组TPH1基因rs623580位点的基因型频率差异(χ2=6.560,P=0.038)和等位基因频率差异(χ2=5.517,P=0.019)具有统计学意义。研究组与对照组按性别分亚组,女性研究组与对照组基因型频率差异(χ2=8.026,P=0.018)和等位基因频率差异(χ2=7.154,P=0.007)具有统计学意义。男性研究组与对照组基因型频率差异和等位基因频率差异不具有统计学意义。结论新疆维吾尔族群体色氨酸羟化酶1基因T3804A位点与抑郁症的发病可能具有关联性,A等位基因可能是抑郁症的易感基因。     

Identification and distribution of tryptophan hydroxylase (TPH)-positive neurons in the planarian Dugesia japonica

We identified a full-length tryptophan hydroxylase (TPH) gene of planarian Dugesia japonica from a head EST database, and named it DjTPH. Based on whole-mount in situ hybridization and immunofluorescence analyses, DjTPH mRNA and protein were mainly expressed in the nervous system, especially ventral nerve cords and eye pigment cells. Furthermore, DjTPH immunoreactivity was clearly detected at commissure axonal connections in the ventral nerve cords. 5-HT was significantly decreased in DjTPH-knockdown planarians compared with control animals. These results suggest that DjTPH is required for 5-HT biosynthesis, and DjTPH antibody is a useful marker for serotonergic neurons in planarians.