抑郁症患者自杀行为与色氨酸羟化酶基因及单胺氧化酶A基因多态性的关联研究

目的:探讨抑郁症患者自杀行为与色氨酸羟化酶(TPH)、单胺氧化酶A(MAOA)基因多态性的相关性. 方法:符合中国精神障碍分类与诊断标准第3版抑郁症诊断标准患者212例,汉密尔顿抑郁量表评分≥17分,其中64例患者有自杀或自杀未遂行为(有自杀行为组),148例患者无自杀行为(无自杀行为组).采用聚合酶链式反应扩增及限制性片段长度多态性技术检测TPH、MAOA基因多态性,与抑郁症患者自杀行为进行关联分析. 结果:TPH基因型频数和等位基因频率上有自杀行为组与无自杀行为组差异有统计学意义(x2=6.058,P=0.048;x2=4.774,P=0.029),有自杀行为组A/A基因型和等位基因A频率分布显著高于无自杀行为组(P＜0.05).MAOA基因型频数和等位基因频率上有自杀行为组与无自杀行为组差异无统计学意义(x2=0.922,0.898;P均＞0.05). 结论:TPH基因多态性与抑郁症患者的自杀行为存在关联,MAOA基因多态性与抑郁症患者自杀行为可能无关联.     

色氨酸羟化酶基因多态性对抑郁症患者额叶亚区改变影响的影像学研究

目的 探讨色氨酸羟化酶(TPH1)基因A218C多态性对抑郁症患者额叶亚区结构、功能的影响.方法 对60例抑郁症患者(患者组)及52名性别、年龄、受教育年限匹配的健康人(对照组)进行磁共振扫描、TPH1基因分型,比较不同诊断组、基因型组内额叶密度、激活强度的差异.结果(1)AA基因型患者组右额下回灰质密度值(1.25±0.03;n=6)较CC基因型对照组(1.37±0.10;n=13)显著降低,差异有统计学意义(F=2.01,P=0.19;经LSD比较,P=0.04).(2)负性面部表情识别时,AA基因型患者组左额下回(0.19±0.31; n=5)激活强度值较AC基因型患者组(-0.03±0.34;n=13)、CC基因型患者组(-0.11±0.46;n=8)、AC基因型对照组(-0.03±0.23; n=18)、CC基因型对照组(-0.07±0.26;n=10)均显著增强,差异均有统计学意义(F=4.47,P=0.00;经SD比较,P分别=0.02,0.03,0.02,0.00);AA基因型对照组左额下回(0.15±0.15,n=6)激活强度值较AC基因型对照组、CC基因型对照组均显著增强,差异均有统计学意义(F=4.47,P=0.00;经LSD比较,P分别=0.02,0.02).同时,AA基因型患者组右额下回(0.33±0.27)激活强度值较其余5组(0.10±0.43; -0.04±0.25;0.05±0.16;0.02±0.28;-0.12±0.31)均显著增强,差异均有统计学意义(F=4.23,P=0.03;经LSD比较;P分别=0.04,0.02,0.04,0.03,0.02).结论 TPH1 A等位基因对抑郁症患者额叶亚区功能有一定程度的损害作用,可能构成抑郁症额叶异常的部分遗传学基础.     

色氨酸羟化酶基因与心境障碍及自杀行为

5-羟色胺(5-HT)系统功能紊乱与负性情感状态有关,包括抑郁、焦虑等.5-HT减少可导致行为脱抑制,在人类可出现冲动攻击行为和反社会行为、自杀以及自杀相关行为.色胺酸羟化酶(tryptophan hydroxylase ,TPH)与苯丙氨酸羟化酶(PAH)、酪氨酸羟化酶(TH)一样是芳香族氨基酸羟化酶大家族的一员.     

色氨酸羟化酶2基因与精神障碍相关研究进展

本文就色氨酸羟化酶2基因与情感情精神障碍、自杀行为、精神分裂症等的相关性作简要综述。     

色氨酸羟化酶基因与抑郁症及自杀行为的关联研究

本文对删基因与抑郁症及自杀行为关联的研究进展作一综述。     

色氨酸羟化酶2基因多态性与强迫症的关联研究

目的 探索汉族人群中具有中枢特异性的色氨酸羟化酶2(TPH2)基因多态性与强迫症的关系.方法 选取TPH2基因转录区的单核苷酸多态rs4570625,采用TaqMan探针SNP基因分型技术测定137例强迫症患者和190名健康人的多态分布. 结果强迫症组色氨酸羟化酶(TPH)-2基因rs4570625G/T多态基因型及等位基因频数多态分布与对照组间有统计学差异 (χ2=9.972,P<0.01;χ2=8.417,P<0.01); GG基因型和G等位基因与强迫症之间存在显著正关联 [比数比(OR)值分别为2.239和1.587].早发型患者组该多态基因型及等位基因频数多态分布与对照组间有显著差异 (χ2=9.202,P<0.05;χ2=8.833,P<0.01); GG基因型和G等位基因与早发型强迫症之间存在显著正关联[OR值分别为2.514和1.886],晚发型患者组与对照组间无统计学差异. 结论在汉族人群中色氨酸羟化酶TPH2基因rs4570625G/T多态可能与强迫症存在遗传关联,GG基因型和等位基因G可能主要是早发型强迫症的风险因子.     

色氨酸羟化酶基因多态性与精神分裂症的关联研究

目的探讨中国汉族人群色氨酸羟化酶(TPH)基因A218C多态性与精神分裂症的关系。方法选取符合美国精神障碍诊断与统计手册第4版(DSM-IV)精神分裂症诊断标准的患者212例和正常对照168名,应用聚合酶链式反应(PCR)扩增及限制性片段长度多态性(RFLP)技术检测TPH基因A218C多态性,比较两组基因型和等位基因频率。结果TPH基因的A218C多态性基因型和等位基因频数在患者组与对照组间的分布差异无统计学意义(P>0.05)。②女性患者等位基因A频率显著高于女性对照组(χ2=4.905,P=0.027,OR=1.637,95%CI:1.057~2.536)。③早发型与晚发型分裂症间基因型和等位基因频率的差异无统计学意义(P>0.05)。④患者组家族史阴性和阳性亚组间的A218C多态性的基因型和等位基因频率的差异无统计学意义(P>0.05)。结论TPH基因A218C多态性等位基因A可能是女性精神分裂症的危险因子。     

精神分裂症伴发2型糖尿病与色氨酸羟化酶基因多态性关联研究

目的：在中国汉族精神分裂症患者中探讨色氨酸羟化酶（TPH）基因A218C（rs1800532）多态性与2型糖尿病共病的关联性。方法：采用聚合酶链反应-限制性片断长度多态（PCR-RFLP）技术在中国汉族人群中对98例伴发2型糖尿病的精神分裂症患者（伴糖尿病组）及109例单纯精神分裂症患者（不伴糖尿病组）进行TPH基因A218C的分型,并进行等位基因及基因型比较。结果：伴糖尿病组与不伴糖尿病组比较,TPH6基因A218C多态性等位基因分布（χ^2=0．00,df=1,P〉0．05）和基因型分布（χ^2=3．78,df=2,P〉0．05）均无显著差异。在男性患者中,伴糖尿病组与不伴糖尿病组基因型分布存在显著差异（χ^2=6．57,df=2,P=0．037）,而等位基因分布（χ^2=1．28,df=1,P=0．26）则无明显差异;在女性患者组中,伴糖尿病组与不伴糖尿病组基因型分布（χ^2=1．54,df=2,P=0．46）和等位基因分布（χ^2=0．02,df=1,P〉0．05）均无显著差异。结论：在中国汉族男性精神分裂症患者中TPH基因A218C多态性与患2型糖尿病存在关联,其可能是男性精神分裂症患者患2型糖尿病的易感基因。     

TPH基因A218C多态性与单相抑郁症及其症状表型的关联分析

目的探讨中国汉族人色氨酸羟化酶(TPH)基因A218C多态性与单相抑郁症及其症状表型的遗传关联性。方法应用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)技术分析TPH A218C基因多态性,对132例抑郁症患者(病例组)和142名正常对照者进行关联分析;采用汉密顿抑郁量表(HAMD)评定病例组症状表型。结果①经吻合度检验,病例组和对照组的观察值与期望值吻合度良好,均符合Hardy-Weinberg平衡法则(2分别为3·65124、3·34227,P分别为0·056027、0·067521)。②病例组与对照组的基因型总体分布的差异无显著性(2=1.0673,df=2,P>0·05);两组在等位基因频率的分布上差异亦无显著性(2=1·2211,df=1,P>0·05)。③病例组中症状表型(7类因子结构)在三种基因型间分布差异无显著性。结论未发现本研究病例组TPH基因A218C多态性与单相抑郁症及其症状表型之间存在关联性。     

色氨酸羟化酶A218C 基因多态性与精神分裂症遗传 关联性研究的Meta 分析

目的 综合分析色氨酸羟化酶（TPH）A218C基因多态性与精神分裂症遗传易感性的关 系。方法 检索国内外数据库中有关精神分裂症与A218C相关性研究的文献,按照纳入与排除标准进 行筛选,获得2017年5月份以前公开发表的病例对照研究的资料,评价文献质量后采用Stata 14.0软件对 A218C多态性做Meta分析。结果 共纳入11个病例对照研究,包括3 419例精神分裂症患者和4 048例 对照。Meta分析显示TPH 218A等位基因能够增加精神分裂症的易感性,但存在种族差异,携带A等位基 因的白种人群罹患精神分裂症的风险更高。结论 TPH A218C基因多态性与精神分裂症相关,可能是发 生该病的危险因素。     

Tryptophan hydroxylase gene and major psychoses

Disturbances of the serotoninergic neurotransmitter system have been implicated in the pathogenesis of mood disorders. The tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, has been recently reported to be associated with bipolar disorder. In this study, we investigated TPH A218C gene variants in a sample of subjects affected by major psychoses. One thousand four hundred and twenty-four inpatients affected by bipolar (n=627), major depressive (n=511), schizophrenic (n=210), delusional (n=48) disorder and psychotic disorder not otherwise specified (n=27) (DSM-IV) were included; all patients and 380 controls were typed for the TPH variants using PCR techniques. A sub-sample of 963 patients was assessed using the Operational Criteria for Psychotic Illness (OPCRIT). TPH variants were not associated with major psychoses, but a trend was observed toward an excess of TPH*A/A in bipolar disorder. The analysis of symptomatology factors did not show any significant difference either; however, a trend was observed for males with the TPH*A genotype to have lower depressive symptoms compared with TPH*C subjects. Possible stratification factors such as current age and age of onset did not affect the observed results. TPH A218C variants are not, therefore, a major liability factor for the symptoms of major psychoses to have in the present sample. TPH*A containing variants may be a protective factor for depressive symptoms among male subjects with mood disorders or for a subtype of mood disorders characterized by a mainly manic form of symptomatology.     

Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors

Serotonergic dysfunction is implicated in mood disorders and suicidal behaviors. Genetic variants of tryptophan hydroxylase (TPH), a rate-limiting enzyme in the biosynthesis of serotonin, were associated with suicidal behaviors in three reports, but were not found in other studies. We investigated the TPH A218C polymorphism in 151 subjects with mood disorders and 200 control subjects. The results demonstrated a significant difference in genotypic distribution between controls and depressed patients, but not bipolar patients. A positive association between TPH polymorphism and suicidal behaviors was found in depressed patients and not in bipolar patients. We suggest that the association of TPH variants and suicide might depend on the diagnosis, and TPH mutation plays no major role in the pathogenesis of bipolar disorders.     

Tryptophan hydroxylase gene and response to lithium prophylaxis in mood disorders.

Lithium is an effective prophylactic agent in mood disorders but not all patients with mood disorders respond to lithium therapy; it is therefore necessary to identify responders prior to treatment. Clinical predictors account for about half of the variance and it is probable that genetic factors play a substantial role. The aim of this study was to investigate the possible association between the tryptophan hydroxylase (TPH) gene and prophylactic efficacy of lithium in mood disorders. One hundred and eight subjects affected by bipolar (n = 90) and major depressive (n = 18) disorder were followed prospectively for an average of 50.4 months and were typed for their TPH variant using polymerase chain reaction techniques. TPH variants were marginally associated with lithium outcome (F = 3.16; d.f.=2,105; P = 0.046). Subjects with the TPH*A/A variant showed a trend toward a worse response compared to both TPH*A/C and TPH*C/C variants. Consideration of possible stratification effects such as gender, polarity or age at onset did not influence the observed association. TPH variants may be a possible factor influencing the prophylactic efficacy of lithium in mood disorders.     

Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD

Genetic and pharmacological studies have emphasised the role of serotonin 5-hydroxytryptamine (5-HT) as a possible etiologic factor in the development of attention-deficit hyperactivity disorder (ADHD). Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin from tryptophan. Originally, the TPH gene was thought to be widely expressed, but a second form of TPH, TPH2, was recently identified and the TPH2 gene was found to be solely expressed in the brain. We examined eight single nucleotide polymorphisms (SNP) in the TPH2 gene for association with ADHD in 179 Irish nuclear families. Transmission disequilibrium test analysis revealed significant association between the T allele of marker rs1843809 with the disorder (chi2=12.2, P=0.0006, OR=2.36). Stratifying data by the sex of the transmitting parent showed that this association was enhanced when paternal transmission was considered (OR=3.7). In addition, several haplotypes (all including the associated marker) were associated with ADHD. These preliminary findings suggest that TPH2 is a susceptibility locus for ADHD. Further confirmation, preferably from different ethnic groups, is required to firmly implicate TPH2 in the pathophysiology of ADHD.     

Tryptophan metabolism in depression

Psychiatric patients suffering from endogenous depression and a control group without endogenous depression were given oral loads of L-tryptophan and urinary excretion determined of the tryptophan metabolites on the pyrrolase pathway: kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid. Female endogenously depressed subjects excreted significantly more kynurenine and 3-hydroxykynurenine but not the subsequent metabolite 3-hydroxyanthranilic acid than did female control subjects. Variability of excretion of kynurenine and 3-hydroxykynurenine at different times by the same subject was much greater in the endogenously depressed than in the control group. There was no consistent temporal relationship between excretion of metabolites and severity of the depressive illness. The possible significance of the findings in relation to defective tryptophan metabolism in the brain in endogenous depression is commented upon.     

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.     

Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated possible relationships between DNA polymorphisms in the tryptophan hydroxylase (TPH) and catechol-O-methyltransferase (COMT) genes and CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 66). Lower CSF 5-HIAA levels were found in men with the TPH U allele (p = 0.005), but not in women. A similar but less significant pattern was observed for CSF HVA. No relationship was found between the TPH polymorphism and CSF MHPG. COMT genotypes did not relate significantly to MM concentrations. The results suggest that TPH genotypes participate differentially in the regulation of serotonin turnover rate under presumed steady state in the central nervous system of men. Due to the uncertain functional relevance of the DNA polymorphism investigated and the many calculations performed, the results should be interpreted with caution until replicated.