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.     

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。     

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.     

原发性失眠的5-羟色胺转运体基因遗传多态性研究

目的　探讨原发性失眠与羟色胺转运体( 5 -HTT)基因遗传多态性的关系。方法　对85例病例组和54名对照组提取外周血基因组DNA ,进行PCR扩增,分析相应的基因型,并比较两组不同基因型患者的焦虑和抑郁评分有无差异。结果　两组的5 -HTTLPR和5 -HTTVNTR的基因型、等位基因频率及不同基因型频率的两两比较均无显著性差异(P >0 .0 5) ;病例组5- HTTLPR的S/S(S组)和S/L +L/L(L组)两组之间及5- HTTVNTR的1 0 / 1 0 + 1 0 / 1 2 ( 1 0组)和1 2 / 1 2 ( 1 2组)两组之间的焦虑、抑郁量表评分比较均无显著性差异(P >0 . 0 5)。结论　5- HTTLPR和5 -HTTVNTR两种基因遗传多态性与原发性失眠的关系尚需进一步探讨。     

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.     

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.     

No association of serotonin transporter polymorphism (5-HTTVNTR and 5-HTTLPR) with characteristics and treatment response to atypical antipsychotic agents in schizophrenic patients

Background

Serotonin transporter is a candidate gene for the pathogenesis of some psychiatric disorders. The aim of this study was to examine the role of the serotonin transporter gene polymorphism in the clinical aspects of schizophrenia including symptomatology and therapeutic response.

Methods

This study comprised 141 unrelated patients who strictly met the DSM-IV criteria for schizophrenia and 115 control subjects. All subjects were of Korean ethnicity. Serotonin transporter intron 2 VNTR polymorphism (5-HTTVNTR) and serotonin transporter linked polymorphic region polymorphism (5-HTTLPR) were analyzed in schizophrenia patients and control subjects. The Positive and Negative Symptom Scale (PANSS) was used at baseline and 6 weeks after atypical antipsychotic treatment to evaluate the clinical symptoms. Body mass index (BMI), the Barnes Akathisia Rating Scale (BARS), the Simpson–Angus Rating Scale (EPS) for adverse effect and the Calgary Depression rating Scale for Schizophrenia (CDSS) were measured.

Results

There were no significant differences in the frequency of genotypes between schizophrenia patients and control subjects. There were no significant differences in PANSS scores before treatment according to the serotonin transporter genotypes. Treatment response after atypical antipsychotics did not differ among the genotypes. No difference was shown among the genotypes for the scales in adverse effects and depression (BMI, BARS, EPS, CDSS).

Conclusions

Our results suggest that the serotonin transporter polymorphism does not seem to be a susceptibility factor for schizophrenia. Similarly, the serotonin transporter polymorphism might not affect the therapeutic response and adverse effect to atypical antipsychotics in Korean patients with schizophrenia. Further studies with a larger number of subjects are required to better understand the role of the serotonin transporter polymorphism in schizophrenia.     

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.     

Interaction between the dopamine D4 receptor and the serotonin transporter promoter polymorphisms in alcohol and tobacco use among 15-year-olds

Early onset of alcohol and tobacco use during adolescence increases the risk for establishing a substance use disorder in adulthood. Both alcohol and nicotine stimulate the dopamine (DA) and the serotonin (5-HT) systems. The DA system has been implicated in the mediation of the rewarding effects of self-administered drugs of abuse. A possible role of an interaction between these neurotransmitter systems in substance use behavior has been suggested but is as yet unknown. The present study was designed to examine the influence of the DA D4 receptor (DRD4) and the serotonin transporter (5-HTT) genotype and their interaction on adolescent alcohol and tobacco experimentation. Participants were from a longitudinal study of a birth cohort consisting initially of 384 children from a high-risk community sample. At the age of 15 years, adolescents completed a self-report questionnaire measuring tobacco and alcohol consumption. DNA was taken from 305 participants (146 boys, 159 girls) and genotyped for the DRD4 exon III and the 5-HTTLPR polymorphisms. The DRD4 7-repeat allele was associated with greater smoking and drinking involvement in boys. In girls, a significant DRD4 × 5-HTT interaction was detected. Girls without the DRD4 7-repeat allele and who were homozygous for the long allele of 5-HTTLPR displayed the highest smoking and drinking activity. The genetic and potential molecular background underlying adolescent vulnerability to substance abuse is discussed.     

Receptor and Transporter Imaging Studies in Schizophrenia,Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology-

Summary: Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D₂ and 5-HT_IA receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D₂ receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D₂ receptor occupancy rates and antipsychotic efficacy has been found. The measurement of S-HT_IA receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT_IA receptor binding potential in schizophrenia. β-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age-and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [¹²⁴I]/β-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the β-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drugnaive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.     

Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response

Serotonin is implicated in the pathogenesis of schizophrenia. Following serotonin release, the serotonin transporter (5-HTT) is the major determinant of serotonin inactivation. The present study tested the hypothesis that a biallelic polymorphism in the 5' regulatory region of the 5-HTT gene (5-HTTLPR) confers susceptibility to schizophrenia, association with the clinical manifestations of schizophrenia or clozapine response. 90 treatment-resistant schizophrenic patients were assessed using the Brief Psychiatric Rating Scale before and after clozapine treatment. The results demonstrated that the 5-HTTLPR variants did not play a major role in the susceptibility, clinical manifestations or clozapine response in schizophrenia.     

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.     

Simultaneous genotyping of multiple polymorphisms in human serotonin transporter gene and detection of novel allelic variants

The serotonin transporter, called SLC6A4, SERT or 5-HTT, modulates neurotransmission by removal of serotonin from the synapse of serotonergic neurons, facilitating serotonin reuptake into the presynaptic terminus. Selective serotonin reuptake inhibitors block the action of the serotonin transporter and are used to treat depression and other neuropsychiatric disorders. Three polymorphisms in the 5-HTT gene have been implicated in treatment response and neuropsychiatric disorders. A 44-bp promoter ins/del polymorphism (5-HTTLPR) produces primarily long and/or short alleles due to either 14 (short) or 16 (long) repeats of variably conserved 20–23 bp units. Also implicated, a 17–18 bp variable number tandem repeat found in intron2 (StIn2) is expressed as triallelic content with 9, 10, or 12 repeats (StIn2.9, StIn2.10 or StIn2.12). Finally, a single nucleotide polymorphism rs25531 located within the promoter polymorphic-linked region alters the function of the long promoter allele. We developed a PCR-based fragment analysis assay, which is analyzed on an ABI sequencer, whereby we are able to detect all three genotypes simultaneously. Using this technique, we identified novel sequences, which demonstrate promoter repeat regions containing (1) a 17 repeat with rs25531 A/G polymorphism, (2) two with 18-repeat units, (3) one with 20-repeat units and (4) a 24-repeat sequence. The novel repeats were confirmed by direct sequencing of gel-purified amplicons.     

5-羟色胺转运体启动子区域基因多态性位点与双相障碍的关联研究

目的:探讨5-羟色胺转运体蛋白基因启动子区域(5-HTTLPR)位点多态性与双相障碍之间的遗传学联系。方法:以中国西北地区汉族人群中51例双相障碍患者(患者组)的核心家系(父母组102名)共153人为研究对象;取每个成员血液样本DNA,应用聚合酶链反应技术扩增5-HTTLPR位点,以琼脂糖凝胶电泳法进行基因分型,对5-HTTLPR位点多态性与双相障碍之间分子遗传学联系进行以家系为基础的连锁不平衡分析。结果:无论5-HTTLPR位点各种基因型(L/L、L/LG、S/L、S/S、S/LG)还是等位基因(L、LG、S)频率在患者组和父母组比较差异无统计学意义(χ2=3.732,P0.05;χ2=0.633,P0.05)。基于基因型的单倍体相对风险分析(GHRR)以及传递不平衡分析(TDT)也未发现5-HTTLPR与双相障碍存在连锁不平衡(GHRR:P0.05;TDT:χ2=2.418,P0.05)。结论:5-HTTLPR多态性位点在中国西北地区汉族人群双相障碍发病机制中不起主要作用,但不能排除微效作用的存在。     

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     

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 gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders

Objective: The functional polymorphism in the promoter region of the SLC6A4/5-HTT serotonin transporter gene (5-HTTLPR) has been linked to altered stress response. Carriers of the short (s-) allele have increased negative psychological reactions and stress hormone release compared with carriers of the long (l-) allele, interacting with severe life events including childhood trauma. High stress levels are associated with cognitive impairments in a variety of clinical and experimental studies. Patients with psychotic disorders are characterized both by more childhood traumatic events and abnormal stress responses and by significant but highly variable cognitive dysfunction. We hypothesize that 5-HTTLPR variations and long-term effects of childhood trauma interact and contribute to some of the variation in cognitive dysfunction seen in patients with psychotic disorders. Methods: Patients with psychotic disorders (schizophrenia and affective spectrums) were recruited from a catchment area–based treatment organization. History of childhood abuse was obtained by the Childhood Trauma Questionnaire. Cognitive function was assessed through a comprehensive, standardized neuropsychological test battery. 5-HTTLPR genotypes were analyzed using standard polymerase chain reaction. Results: We observed a significant interaction between 5-HTTLPR variants and childhood trauma across cognitive domains; here, homozygotic s-carriers exposed to high levels of childhood trauma (physical neglect and abuse) had significantly poorer cognitive functioning than all other groups. Conclusions: Our results need replication but underline the importance of investigating childhood trauma and its interaction with genetic markers when studying cognitive dysfunction in patients with psychotic disorders.