Possible association between serotonin transporter promoter region polymorphism and extremely violent crime in Chinese males

The neurotransmitter, serotonin, has been implicated in aggressive behavior. The serotonin transporter (5-HTT), which reuptakes serotonin into the nerve terminal, plays a critical role in the regulation of serotonergic function. Previous western reports have demonstrated that the low-activity short (S) allele of the 5-HTT gene-linked polymorphic-region (5-HTTLPR) polymorphism is associated with aggressive behavior and associated personality traits. In the present study, we investigated this 5-HTTLPR genetic polymorphism in a group of Chinese males who had been convicted for extremely violent crime (n = 135) and a normal control group (n = 111). The proportion of S-allele carriers was significantly higher in the criminal group than in the controls (p = 0.006). A significant association was not demonstrated for the relationship between the 5-HTTLPR polymorphism and antisocial personality disorder, substance abuse or alcohol abuse in the criminal group. Our findings demonstrate that carriage of the low-activity S allele is associated with extremely violent criminal behavior in Chinese males, and suggests that the 5-HTT may be implicated in the mechanisms underlying violent behaviors.     

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 polymorphism (5‐HTTLPR) association with melancholic depression: a female specific effect?

Earlier studies yielded inconsistent results on the association between variation in the serotonin transporter (5-HTT) gene and depression, with evidence for a differential effect of the 5-HTTLPR on melancholic versus atypical depression. To further delineate the impact of 5-HTT gene variation on psychopathology in depression, in this analysis the influence of the 5-HTTLPR and the functionally closely related 5-HTT rs25531 was investigated in 340 Caucasian patients with a major depressive episode (DSM-IV) with particular attention to the subtype of depression (melancholic depression versus atypical depression) applying logistic regression models adjusted for age and gender. The homozygous, more active 5-HTTLPR LL genotype was significantly associated with melancholic depression (odds ratio, OR, 1.7; 95% confidence interval, CI, 1.1-2.6; P=0.04), with the effect originating in the female subgroup of patients (OR 1.9; 95%CI 1.0-3.4; P=0.05). Also, the more active 5-HTTLPR/5-HTT rs25531 haplotype L(A)L(A) conveyed a significant risk for melancholic depression (OR 2.0; 95%CI 1.3-3.1; P=0.001), again only in the female subsample of patients (OR 2.1; 95%CI 1.1-4.1; P=0.02). The present results provide further support for an association of genetic variation increasing serotonin transporter activity with the melancholic subtype of depression as well as evidence for a potential female-specific mechanism underlying this effect.     

Serotonin transporter gene polymorphism and BPSD in mild Alzheimer's disease

The purpose of the present study was to confirm an association of functional polymorphism within the serotonin transporter (5-HTT) gene with Alzheimer's disease (AD) and behavioral and psychological symptoms of dementia (BPSD) in mild AD. Apolipoprotein E (ApoE) gene polymorphism and 2 types of functional polymorphism in the 5-HTT gene, 5-HTT-linked polymorphic region (5-HTTLPR) and a 5-HTT variable number of tandem repeats sequence (5-HTTVNTR) were analyzed longitudinally in outpatients with mild AD to find out whether there was a relation between any such polymorphisms and the occurrence of BPSD. No significant differences in genotype distribution or allele frequencies were identified for 5-HTTLPR or 5-HTTVNTR between AD patients and age- and sex-matched non-demented controls regardless of ApoE epsilon4 allele. No significant differences were noted in 5-HTTLPR genotype or allele distributions between AD patients with or without BPSD. However, significant associations were observed between presence of 5-HTTVNTR allele 10 and BPSD or aggressiveness. This difference was independent of the presence of the ApoE epsilon4 allele. As a result, 5-HTT polymorphisms are unlikely to play any substantial role in susceptibility to AD. Conversely, 5-HTTVNTR influences the risk of developing BPSD or aggressiveness and genetic variations in the 5-HTT gene may be involved in the development of symptomatology for mild AD.     

Serotonin transporter gene polymorphisms: effect on serotonin transporter availability in the brain of suicide attempters

The efficacy of serotonin reuptake inhibitors in depression and anxiety disorders suggests the gene coding for the serotonin transporter (5-HTT), SLC6A4, as a candidate of importance for these conditions. Positive findings regarding associations between polymorphisms in SLC6A4 have been reported, indicating that these polymorphisms may influence anxiety-related personality traits, as well as the risk of developing depression and suicidality. Serotonin 5-HTT availability was assessed with single photon emission computed tomography (SPECT), using (123)I-beta-CIT as ligand, in a population of unmedicated male suicide attempters (n=9) and in matched controls (n=9). Two polymorphisms in SLC6A4 were assessed, including the 5-HTTLPR located in the promoter region and a variable number of tandem repeats (VNTR) polymorphism in intron 2 (STin2). In suicide attempters, but not in controls, low 5-HTT availability was associated with the S allele of 5-HTTLPR and with the 12 repeat allele of STin2. Data suggest that polymorphisms in SLC6A4 may influence the expression of the brain serotonin transporter in suicide attempters.     

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.     

STin2 variant and family history of suicide as significant predictors of suicide completion in major depression.

BACKGROUND: Suicide is the most serious outcome of major depression, yet not all depressed patients will commit suicide. Genes, along with other factors, might account for this difference. Serotonergic alterations have been observed in suicide and depression and impulsive-aggressive behaviors. Therefore, we aimed to identify predictors of suicide, considering genetic variation at the serotonin transporter (5-HTT) gene. METHODS: We investigated the 5-HTT gene-linked polymorphic region (5-HTTLPR) and intron 2 (STin2) variants of this gene and their relationship to behavioral and clinical risk factors for suicide in a sample of depressed suicides (n =106) and depressed control subjects (n =152), diagnosed by means of proxy-based interviews. RESULTS: We found a significant association of suicide completion with having at least one copy of the STin2 10 allele [chi(2)(1) = 10.833, p = .002]. No differences were found for the 5-HTTLPR variable number of tandem repeats. After controlling for behavioral and clinical risk factors for suicide, the STin2 variant remained a significant predictor of suicide in major depression when jointly considered with a family history of suicide (odds ratio 5.560, 95% confidence interval 1.057-29.247). CONCLUSIONS: The STin2 locus might account, at least in part, for the observed familial aggregation of suicidal behavior. These results should be further explored in families where clustering of suicidal behavior is observed.     

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。     

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。     

Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients

Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTT sites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD.     

Association of D4 dopamine receptor gene and serotonin transporter promoter polymorphisms with infants' response to novelty

Effects of DRD4 and 5-HTTLPR length polymorphisms have been reported on neonatal and infant temperament as well as adult personality traits. The 7-repeat form of the DRD4 III exon VNTR polymorphism has been associated with childhood ADHD, and recently we have reported its link with attachment disorganization in a nonclinical population of infants. Here, we report associations of these polymorphisms with infant temperament at 12 months of age. Maternal accounts of temperament and observed response to novelty were investigated for 90 infants, who were independently genotyped for the DRD4 III exon, and for 5-HTT-linked promoter region length polymorphisms. Maternal rating of temperament was not affected by these polymorphisms, but we found combined genotype effects for infants' observed responses to a novel, anxiety-provoking stimulus: the appearance of, and approach by, a stranger. Infants with at least one copy of both the 7-repeat DRD4 allele and the long variant of 5-HTTLPR (7(+), l/l&l/s) responded with significantly less anxiety than infants with other genotypes. However, infants with the 7-repeat DRD4 allele and homozygous for the short form of 5-HTTLPR (7(+), s/s) showed more anxiety and resistance to the stranger's initiation of interaction. These genotype effects were not redundant with the previously reported association between the 7-repeat DRD4 allele and disorganized attachment behavior. Although both temperament and attachment behavior were affected by the DRD4 repeat polymorphism, the effect on temperament measures was modified by the infants' 5-HTTLPR genotype.     

Association between suicide attempts and 5-HTTLPR-S-allele in alcohol-dependent and control subjects: further evidence from a German alcohol-dependent inpatient sample.

BACKGROUND: Genetically-mediated alterations in serotonergic transmission have been implicated in both the pathogenesis of alcoholism and suicidal behavior. Thus, the identification of vulnerability genes could uncover pathophysiological links for both syndromes. A significant association between suicide attempts and the 5-HTT promoter polymorphisms (5-HTTLPR) S-allele has been reported in a sample of French alcohol-dependent subjects, and this paper evaluates this phenomenon in a German sample. METHODS: One hundred and sixty-three patients meeting DSM-IV criteria for alcohol dependence and 117 healthy controls were investigated. Blood samples were taken to genotype the 5-HTTLPR by using polymerase chain reaction (PCR) of lymphocyte DNA. RESULTS: 5-HTTLPR-S alleles were seen more frequently in suicidal compared to nonsuicidal alcohol-dependent subjects. Furthermore, significant effects from suicide attempts on the number of S-alleles were found. CONCLUSIONS: The results are consistent with an association between the 5-HTTLPR-S-allele and suicide attempts in alcohol-dependent subjects.     

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.     

Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), [3H]paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity

The aim of this study was to investigate [3H]paroxetine binding and impulsivity in alcohol-dependent and age-matched control subjects in relation to a 5'-promoter region serotonin transporter (5-HTT) polymorphism (5-HTTLPR). Alcohol-dependent subjects were hypothesized to show a decreased number of bindings sites and a lower dissociation constant. 5-HTTLPR S-genotype carriers in both alcohol-dependent and control subjects were expected to show significantly fewer binding sites and a lower dissociation constant. Influences of impulsive traits, chronic daily alcohol intake, duration of alcohol dependence, age of onset and age on [3H]paroxetine binding were also investigated. Inpatients meeting DSM IV alcohol dependence criteria and of German descent were recruited to avoid ethnic stratification effects. One hundred and seventeen control subjects of similar social status were recruited from a town community. Blood samples were taken from both alcohol-dependent and control subjects to determine 5-HTTLPR genotypes using PCR of lymphocyte DNA, and to perform platelet [3H]paroxetine binding (binding capacity: B(max); and dissociation constant: K(D)). Impulsivity was assessed using the Barratt impulsiveness scale version 5 (BIS-5) in alcohol-dependent subjects only. Alcohol-dependent subjects were subdivided into low or high impulsivity groups using a median-split of the BIS-5 scale. The control group was slightly older than the alcohol-dependent group (not statistically significant). [3H]paroxetine binding was investigated in 72 control subjects and 72 patients, of which five patients met type 2 alcohol dependence criteria. Genotyping was carried out in all patients and control subjects. A significant influence of duration of alcohol dependence was found on the [3H]paroxetine binding K(D) but not B(max.) Neither alcohol-dependent nor control subjects showed any differences in B(max) or K(D). S-allele carriers did not show a decreased binding or lower dissociation constant. Furthermore, no significant interaction between B(max) and K(D) with either 5-HTTLPR genotype or impulsivity was revealed. This was the first study to investigate platelet [3H]paroxetine binding in alcohol-dependent and age-matched control subjects in relation to the 5-HTTLPR genotype. No differences concerning 5-HTTLPR-alleles were found in these groups Furthermore, no significant interaction between these parameters and impulsivity was shown in alcohol-dependent subjects. These results do not support previous results of altered [3H]paroxetine binding sites in alcohol-dependent subjects or 5-HTTLPR S-allele carriers. K(D) might be influenced by duration of alcohol dependence, but not sufficiently to yield differences between alcohol-dependent and control subjects.     

The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity

Strong evidence links the 5-HTTLPR genotype to the modulation of amygdala reactivity during fear conditioning, which is considered to convey the increased vulnerability for anxiety disorders in s-allele carriers. In addition to amygdala reactivity, the 5-HTTLPR has been shown to be related to alterations in structural and effective connectivity. The aim of this study was to investigate the effects of 5-HTTLPR genotype on amygdala reactivity and effective connectivity during fear conditioning, as well as structural connectivity [as measured by diffusion tensor imaging (DTI)]. To integrate different classification strategies, we used the bi-allelic (s-allele vs l/l-allele group) as well as the tri-allelic (low-functioning vs high-functioning) classification approach. S-allele carriers showed exaggerated amygdala reactivity and elevated amygdala-insula coupling during fear conditioning (CS + > CS−) compared with the l/l-allele group. In addition, DTI analysis showed increased fractional anisotropy values in s-allele carriers within the uncinate fasciculus. Using the tri-allelic classification approach, increased amygdala reactivity and amygdala insula coupling were observed in the low-functioning compared with the high-functioning group. No significant differences between the two groups were found in structural connectivity. The present results add to the current debate on the influence of the 5-HTTLPR on brain functioning. These differences between s-allele and l/l-allele carriers may contribute to altered vulnerability for psychiatric disorders.