5-羟色胺基因多态性与抑郁症的相关性研究

目的：探讨5-羟色胺转运体(5-HTT)基因启动子区多态性(5-HTTLPR)与抑郁症的相关性及其对抗抑郁药疗效的影响。方法：运用聚合酶链反应技术(PCR)检测51例抑郁症患者(患者组)和60名健康对照者(对照组)5-HTTLPR的分布频率；并予文拉法辛治疗，用汉密尔顿抑郁量表(HAMD)观察疗效。结果：患者组5-HTTLPR的短重复序列／短重复序列(short／short，S／S)基因型和短重复序列(short，S)等位基因频率分别为71％和81％，对照组为45％和69％差异显著。治疗4周后，长重复序列／长重复序列(long／long，L／L)基因型患者的减分率显著高于其他两型。结论：5-HTTLPR的S／S基因型可能是抑郁症的易感基因之一，L／L基因型可能和更好的选择性5-羟色胺受体阻滞剂类(SSRIs)疗效有关。     

Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study.

BACKGROUND: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS: The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.     

How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure

The serotonin transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene is associated with amygdala response during negative emotion. The aim of this study was to investigate whether this genotype effect on amygdala function is mediated by current serotonin transporter (5-HTT) levels or rather by genetically induced influences during neurodevelopment, shaping brain structure. A total of 54 healthy subjects underwent functional and structural magnetic resonance imaging, [¹¹C]DASB positron emission tomography and 5-HTTLPR genotyping to analyze the interrelationships between amygdala activation during processing of unpleasant stimuli, 5-HTTLPR genotype, amygdala volumes and 5-HTT levels in the midbrain and in other brain regions. In line with previous research, carriers of the short allele (S) showed increased amygdala activation. Path analysis demonstrated that this genotype effect was not procured by current 5-HTT availability but by amygdala structure, with smaller amygdala volumes in the S than in the LL genotype, as well as smaller volumes being associated with increased amygdala activation. Our findings stress the role of genetic effects during neurodevelopment.     

The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism

The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case–control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery–Åsberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.     

The effect of 5-HTT gene promoter polymorphism on impulsivity depends on family relations in girls

The short (S) allele of the 5-HTT gene promoter region polymorphism (5-HTTLPR), in combination with adverse environmental influence, leads to higher likelihood of depression. Impulsivity has been related to low serotonin turnover, poor regulation of affect, and problems in the family, including child maltreatment. The current study explored the effect of the 5-HTTLPR polymorphism in the serotonin transporter gene and adverse family environment on impulsivity in adolescents. Healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study (n=483) filled the Adaptive and Maladaptive Impulsivity Scale (AMIS), Barratt Impulsiveness Scale (BIS-11), a scale measuring family relations, and were genotyped. While genotype alone was not associated with thoughtlessness, BIS-11 impulsiveness, fast decision-making or excitement seeking, 5-HTTLPR S allele carriers, however, had higher scores of disinhibition. In girls carrying the S allele, scores of thoughtlessness and disinhibition depended on family relations, being higher with less warmth in the family. Adverse family relations had no effect on impulsivity in girls with LL genotype. In boys, the effects of family relations on maladaptive impulsivity did not depend on genotype. However, the S allele and high maltreatment in the family both independently increased disinhibition and the BIS-11 score in boys. Family environment and the 5-HTTLPR genotype had no interactive effect on excitement seeking or fast decision-making. In summary, carrying the S allele may lead to high maladaptive impulsivity due to higher sensitivity to environmental adversity, which is more significantly expressed in girls.     

Specific personality traits and dopamine, serotonin genes in anxiety-depressive alcoholism among Han Chinese in Taiwan

BACKGROUND: Cloninger [Cloninger CR. 1987. Neurogenetic adaptive mechanisms in alcoholism. Science 236: 410-416.] had proposed a psychobiological model suggesting that three main personality dimensions distinguish the alcoholism into two subtypes (type I and type II). However, the classification was equivocal for clinical diagnosis. Recently, anxiety-depressive alcohol dependence (ANX/DEP ALC) has been posited as a genetically specific subtype of alcoholism. Its clinical characteristics were similar to individuals with type I alcoholism [Cloninger, C.R. 1987. Neurogenetic adaptive mechanisms in alcoholism. Science 236: 410-6.] such as having a high comorbidity with mood disorder, late-onset and more anxious/depressed traits. We attempted to investigate whether the dopamine D2 receptor (DRD2) and the serotonin transporter promoter region (5-HTTLPR) genes were involved in Novelty Seeking (NS) and Harm Avoidance (HA) of ANX/DEP ALC. METHODS: We recruited 46 pure alcohol dependents (Pure ALC) and 87 anxiety-depression alcohol dependents (ANX/DEP ALC). All participants were diagnosed by DSM-IV criteria, genotyped by the PCR method and assessed with Tridimensional Personality Questionnaire (TPQ). RESULTS: Both NS and HA were high in ANX/DEP ALC (p = 0.021; p = 0.001, respectively). The association between NS and ANX/DEP ALC only existed in subjects with DRD2 TaqI A1(+) allele (A1/A1 or A1/A2 genotypes) (p = 0.004) and in those with S/S genotype of 5-HTTLPR (p = 0.005). With the stratification of DRD2 TaqI A1(+) allele, high NS of ANX/DEP ALC existed only in carriers of 5-HTTLPR S/S genotype (p=0.001). Moreover, ANX/DEP ALC was related to high HA only in samples carrying 5-HTTLPR S/L or L/L genotype (p = 0.02). CONCLUSIONS: These findings provided the empirical genetic characterization of the specific personality traits in ANX/DEP ALC among Han Chinese population in Taiwan.     

Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.

BACKGROUND: Recent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding. METHODS: Data were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols. RESULTS: One-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed. CONCLUSIONS: This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.     

中国汉族人群5-羟色胺转运体基因多态性与非病灶性颞叶癫痫的关联性

目的　初步探讨颞叶癫痫(temporal lobe epilepsy,TLE)的遗传易感因素。方法　采用聚合酶链反应技术,检测263例TLE患者和296名健康对照者的5-羟色胺转运体(5-hydroxytryptamine transporter,5-HTT) 基因启动子的基因连锁多态区(gene-linked polymorphic region,LPR) 和第2内含子的可变数目串联重复区(variable number tandem repeat,VNTR) 多态性,分别对所得基因型和等位基因的频率进行相关统计学分析。结果　TLE患者5-HTTLPR多态性的基因型和等位基因频率与正常对照组之间的差异无统计学意义(P>0.05)。TLE患者的5-HTTVNTR的基因型12/12频率高于正常对照组(P<0.01),其等位基因12的频率高于正常对照组(P< 0.01)。携12等位基因者患TLE的相对危险度(OR)是1.435,95%可信区间(CI)为1.096～1.880(P<0.05)。 结论　5-HTTLPR可能不是TLE患者的遗传位点,第2内含子VNTR的等位基因12可能与TLE有一定的关联。     

The 5-HTTLPR polymorphism in South African healthy populations: a global comparison

The serotonin transporter promoter length polymorphism (5-hydroxytryptamine transporter length polymorphism, 5-HTTLPR) in serotonin transporter gene has been implicated in numerous psychiatric disorders. Having a high affinity for the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), serotonin transporter controls the duration, availability and signaling capacity of 5-HT in the synapse. Association studies have focused extensively on this polymorphic region as the frequencies of long- and short-alleles of this gene differ greatly amongst populations and association studies have either reported conflicting results or nothing significant at all. In this study, the genotype and allele frequencies of 5-HTTLPR polymorphism were determined in the healthy South African (SA) individuals belonging to diverse ethnic backgrounds. Cheek cell samples were collected from the three major ethnic groups namely: Caucasians, Africans and coloreds/Mixed population. The DNA was extracted and genotyped for the 5-HTTLPR. Genotypes were compared amongst the three major ethnic groups from SA as well as to that of other studies around the world. This is the first study to report significant differences in the 5-HTTLPR genotype and allelic frequencies among various ethnic groups in SA. Future studies will target larger population groups and the estimation of frequency of these alleles in individuals with autism.     

Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer's disease

A well-known example for gene x environment interactions in psychiatry is the one involving the low activity (s) allelic variant of the serotonin transporter (5-HTT) promoter polymorphism (5-HTTLPR) that in the context of stress increases risk for depression. In analogy, 5-HTT knockout rodents are highly responsive to early life, but also adult external stressors, albeit conflicting data have been obtained. In our study on emotion and cognition using homozygous 5-HTT knockout (5-HTT^−/−) and wild-type (5-HTT^+/+) rats we have been confronted with animal facility construction, which were associated with severe lifetime stress (noise and vibrations). To assess the impact of construction stress on well-established 5-HTT^−/− rat phenotypes we conducted ad hoc analyses of 5-HTT^−/− and 5-HTT^+/+ rats that grew up before and during the construction. The reproductive capacity of the parents of the experimental 5-HTT^+/− rats was significantly decreased. Further, 5-HTT^−/− anxiety-related phenotypes in the elevated plus maze and social interaction tests were abolished after construction noise exposure, due to increased anxiety in 5-HTT^+/+ rats and decreased anxiety in 5-HTT^−/− rats (social interaction test only). In addition, reversal learning was improved in 5-HTT^+/+ and, to a milder extent, decreased in 5-HTT^−/− rats. Finally, construction stress genotype-independently increased behavioural despair in the forced swim test. In conclusion, severe construction stress induces 5-HTT genotype-dependent ‘for-better-and-for-worse’ effects. These data importantly contribute to the understanding of 5-HTT gene x environment interactions and show the risk of losing genotype effects by construction stress.     

Serotonin transporter promoter variants: Analysis in Indian autistic and control population

Serotonin transporter (5-HTT) is a transmembrane protein belonging to Na+/Cl- dependent membrane transporter family and transports 5-HT across the membranes of presynaptic neurons. 5-HTT-linked polymorphic region (5-HTTLPR) gained much interest because of the differential regulation of expression and activity of 5-HTT by its various genotypes. A population-based study has been conducted on 5-HTTLPR with 358 individuals, which included 79 autistic probands, 136 parents, and 143 controls from two subpopulations of east and northeast regions of India. The genotypic frequencies of all the groups conform to Hardy-Weinberg equilibrium. With the finding of efficacy of serotonin reuptake inhibitors in ameliorating ritualistic behavior in autistic disorder, 5-HTT emerged as a putative candidate gene for autism and association studies have been carried out in different ethnic populations. But these studies were inconclusive due to conflicting results on association. Because such a study has never been performed in the Indian population, we have tested the possible involvement of 5-HTTLPR polymorphism with autism. The present study failed to establish any association or linkage of 5-HTTLPR with autism in the Indian population by case-control studies (chi2 = 1.314, P = 0.63) and family-based approaches (TDT chi2 = 0.22, P = 0.64 and HHRR-chi2 = 0.25, P = 0.61). However, when a meta-analysis of all the available TDT data, inclusive of the present study is carried out, we observed a significant preferential transmission of S-allele from parents to the affected offspring (chi2 = 7.51, P = 0.006) indicating an association of 5-HTTLPR with autism.     

Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes

BACKGROUND: The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs. METHODS: In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects. CONCLUSION: Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.     

Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene

A possible dysregulation of serotonergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses. In the present study we analysed allelic and genotypic variations of a recently described functional polymorphic region in the promoter of the human serotonin transporter gene (5-HTTLPR) and a variable tandem repeat (VNTR) in intron 2 of the 5-HTT gene. We investigated 413 unrelated individuals, 180 schizophrenic patients and 233 blood donors as controls. With regard to the 5-HTTLPR, both the schizophrenic and the control group did not significantly differ between genotype frequencies (χ², p = 0.920) and allele frequencies (χ², p = 0.836). The odds ratio for subjects with schizophrenia who were homozygous for the short allele was 1.04 (95% CI 0.59–1.84). No evidence of allelic association to specific schizophrenia subtypes was found. The 5-HTT associated VNTR also showed no significant differences between either the allelic or the genotypic distributions. Haplotype analysis revealed a significant overall linkage disequilibrium at a level of p = 0.00004. Our findings indicate that both polymorphisms are unlikely to play a substantial role in the genetic predisposition to schizophrenic disorders. Received: 14 April 1997 / Accepted: 16 October 1997     

广泛性焦虑障碍与5-羟色胺转运体基因多态性的相关研究

目的　探讨广泛性焦虑障碍与 5 羟色胺转运体 (5 HTT)基因启动子区和内含子 2区两种多态性的相关性。方法　运用聚合酶链反应技术检测 4 7例广泛性焦虑障碍患者 (患者组 )和 90名健康对照者 (对照组 )两种基因多态性的分布频率。结果　患者组启动子区多态性 (5 HTTLPR)的short/short(SS)基因型和short(S)等位基因频率分别为 72 %和 83% ,对照组SS基因型和S等位基因频率分别为 4 9%和 71% ,两组间的差异有显著性 (P <0 0 5 )。内含子 2区数目可变的顺向重复多态性各基因型 (12 / 12 ,12 / 10 ,10 / 10 )频率在患者组中分别为 72 % ,2 6 % ,2 % ,在对照组中分别为 78% ,2 1% ,1% ,两组间的差异无显著性 (P >0 0 5 ) ;等位基因频率比较的差异亦无显著性 (P >0 0 5 )。结论　 5 HTTLPR的SS基因型可能是广泛性焦虑障碍的易感基因之一。     

Serotonin Transporter Gene Polymorphism and Schizoid Personality Traits in Patients with Psychosis and Psychiatrically Well Subjects

Background and Objectives: Serotonin transporter (5-HTT) gene allelic variants were shown to be associated with Neuroticism and Harm Avoidance but the results were not replicated in other studies. The current investigation was undertaken in a further attempt to study the relationship between 5-HTT polymorphism and personality traits.

Subjects and Methods: To evaluate a spectrum of personality traits, MMPI was administered to a sample including patients with affective disorders (n=114), patients with schizophrenia spectrum illnesses (n=110) and psychiatrically well controls (n=124). All groups were genotyped for VNTR-17 and functional insertion-deletion (5-HTTLPR) polymorphisms.

Results: An association was found between 5-HTTLPR polymorphism and scores on three MMPI scales: Psychopathic deviance, Paranoia and Schizophrenia in patients with affective disorders and Schizophrenia in normal subjects. Both affected and control individuals with ‘ss’ genotype exhibited lower scores on these scales.

Conclusion: We demonstrated that functional deletion/insertion allelic variation associated with decreased expression of serotonin transporter (‘s’ allele or ‘ss’ genotype) may restrict expression of schizoid traits in normal subjects and patients with affective disorders.     

A novel allele in the promoter region of the human serotonin transporter gene

The human serotonin transporter (hSERT) gene is a promising candidate for mediating the genetic susceptibility for various psychiatric conditions such as mood and obsessive-compulsive disorders. Two polymorphic sites in this gene attracted much interest: a VNTR of 17-bp repeats in intron two, and an insertion/deletion in the 5'-flanking promoter region (5-HTT gene-linked polymorphic region-5-HTTLPR) creating a short (S) and a long (L) allele. The 5-HTTLPR polymorphism is situated in a GC-rich region composed of 20-23 bp repeating units. The S and L alleles have 14 and 16 repeat-elements respectively. Positive associations of the 5-HTTLPR polymorphism with mood disorders, anxiety-related personality traits, autism and late-onset Alzheimer's disease have been published, although some non replications were also reported. Here we report a novel allele (termed LJ) in the 5-HTTLPR site. This allele is longer than the L allele by 43 bp, has 18 repeat units and contains two copies of the insertion/deletion sequence arranged in tandem. The LJ allele was found in individuals of Libyan and Tunisian Jewish origin but not in Moroccan or Ashkenazi Jews.     

Association analysis between gene variants of the tyrosine hydroxylase and the serotonin transporter in borderline personality disorder

Abstract

objectives. For patients with borderline personality disorder (BPD), we previously reported an independent effect of the catechol-o-methyl-transferase (COMT) low-activity (Met¹⁵⁸) allele and an interaction with the low-expression allele of the deletion/insertion (short/long or S/L, resp.) polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR). The purpose of the present study was to extend these findings to the tyrosine hydroxylase (TH) Val⁸¹Met single nucleotide polymorphism (SNP), the 5-HTTLPR S/L polymorphism incorporating the recently described functional A/G SNP within the long allele of the 5-HTTLPR (rs25531) as well as the variable number of tandem repeat (VNTR) polymorphism within intron 2 of the serotonin transporter gene (STin2). Methods. In 156 Caucasian BPD patients and 152 healthy controls, we tested for association between BPD and the TH Val⁸¹Met SNP, the 5-HTTLPR/rs25531 polymorphism, the STin2, the interaction of the TH Val⁸¹Met SNP with the tri-allelic 5-HTTLPR/rs25531, the interaction of the TH Val⁸¹Met SNP with STin2. Results. Between BPD patients and controls, we observed a slight over-representation of the TH Met⁸¹Met genotype in BPD patients compared to controls, but no statistically significant differences in genotype distribution of the individual markers after adjusting for multiple testing. Logistic regression analysis showed a lack of interaction between the TH Val⁸¹Met and the 5-HTTLPR/rs25531 as well as between the TH Val⁸¹Met and the STin2 polymorphism. Conclusions. These data do not suggest independent or interactive effects of the TH Val⁸¹Met, the 5-HTTLPR/rs25531, or the STin2 polymorphisms in BPD.     

儿童孤独症与5-羟色胺转运体基因连锁多态性区域的关联性研究

目的:探讨汉族人群中5-羟色胺转运体基因连锁多态性区域(5-HTTLPR)与儿童孤独症(CA)的相关性. 方法:采用病例对照研究、聚合酶链反应(PCR)的方法对中国汉族CA患儿与5-HTTLPR的关联性进行研究.以健康儿童作对照. 结果:中国汉族CA患者的5-HTTLPR分布与对照组差异无显著性,但CA组5-HTTLPR纯合子基因型的频率显著高于对照组;5-HTTLPR的基因型与CA的躯体运动因子显著相关. 结论:5-HTTLPR与CA的主要症状存在显著关联;5-HTTLPR的纯合子基因型和等位基因L可能增加了CA的患病危险.