5-HTTLPR polymorphism is associated with nostalgia proneness: The role of neuroticism

Nostalgia, a sentimental longing for the past, is a self-relevant and social emotion. Nostalgia proneness is associated with alleviation of distress or instability (e.g., neuroticism). Although nostalgia proneness is heritable, the specific molecular contributors to this heritability are unknown. We focused on a polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) as a possible biological basis of nostalgia proneness, because the serotonin system has been associated with sensitivity to negative experience. Participants (N = 397 adults) who had reported levels of nostalgia proneness were genotyped. A subsample also completed a measure of neuroticism. Participants with the 5-HTTLPR short allele were higher on nostalgia proneness than those without this allele. Neuroticism mediated the relation between 5-HTTLPR and nostalgia proneness. These findings enrich our understanding of the genetic and personality underpinnings of nostalgia.     

中国汉族人群5-羟色胺转运体基因多态性与神经性厌食的关联研究

目的:探讨中国汉族人群5-羟色胺转运体基因启动子区域(5-HTTLPR)多态性与神经性厌食的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对198例神经性厌食患者和225例正常健康对照者进行基因分型和关联分析。结果:①5-HTTLPR基因的3种基因型S/S、L/S和L/L在神经性厌食组的分布频率分别为65.7%、26.8%、7.6%,对照组为48.8%、37.8%、13.4%,两组差异有统计学意义(P<0.05)。等位基因S、L在神经性厌食组的分布分别为79.0%、21.0%,对照组为69.3%、30.7%,差异有统计学意义(P<0.05)。患病与携带L等位基因成负关联(OR=0.52,95%CI:0.35～0.77),患病与L/S基因型成负关联(OR=0.52,95%CI:0.34～0.79)。②5-HTTLPR功能三等位基因型(LA/LA、S/LA+LA/LG、S/S+S/LG+LG/LG)在神经性厌食组分布频率分别为2.0%、12.2%、85.8%,对照组为4.1%、23.4%、72.5%,两组差异有统计学意义(P<0.05)。患病与携带LA等位基因成负关联(OR=0.44,95%CI:0.25～0.77),患病与S/LA基因型成负关联(OR=0.44,95%CI:0.24～0.81)。结论::5-HTTLPR基因启动子区域多态性与中国汉族人群AN可能存在关联,L、LA等位基因及L/S、S/LA基因型为AN患病的保护等位基因及基因型。     

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S′ allele carriers relative to L_AL_A individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S′ carriers exhibited a more negative association relative to L_AL_A individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.     

Male-specific association between the 5-HTTLPR S allele and suicide attempts in alcohol-dependent subjects

Changes in serotoninergic neurotransmission have been implicated in the pathogenesis of suicidal behavior and alcohol dependence. Previous studies have demonstrated an association between suicide attempts and the 5-HTTLPR S allele in alcohol-dependent subjects. We investigated the frequency of the S allele of 5-HTTLPR in a sample of 100 French Caucasian alcohol-dependent inpatients (48 men and 52 women) with and without a history of suicide attempts. The frequencies of 5-HTTLPR genotypes did not differ significantly between men and women. A history of at least one suicide attempt was more frequent in women than in men (57.5% versus 31.3%, respectively, p=0.008). Logistic regression analysis showed that the presence of the S allele of 5-HTTLPR was related to a life-time risk of suicide attempts, but only in male subjects (p=0.05). There seems to be an allelic association between the 5-HTTLPR S allele and suicidal behavior in alcohol-dependent subjects, but this relationship is restricted to male subjects.     

5-HTTLPR与卒中后抑郁及单相抑郁病因和疗效的关联分析

目的 探讨我国汉族人群卒中后抑郁（post-stroke depression,PSD）及单相抑郁（unipolar depression,UD）患者病因和疗效与5-羟色胺转运蛋白启动子区基因多态性（serotonin transporter gene-linked polymorphic,5-HTTLPR）之间的关系。方法 以4 5例P S D及41例U D患者作为研究对象,以149名正常人作对照,应用聚合酶链式反应（polymerase chain reaction,PCR）扩增技术测定所有研究对象的5-HTTLPR的基因型和等位基因,PSD和UD患者组患者使用氟西汀治疗12周,在基线及12周治疗末时使用汉密尔顿抑郁量表（Hamilton depressive scale,HAMD）-17项评定疾病严重程度及疗效。结果 5-HTTLPR的3种基因型（S/S、S/L和L/L）和等位基因（S和L）在PSD组、UD组和正常对照组之间的分布差异无统计学意义;PSD和UD组S/S纯合子与S/L杂合子及L/L纯合子的基线评分相比差异具有统计学意义;12周治疗后两组患者治愈组和未治愈组之间S/S与S/L和L/L基因型、S和L等位基因分布具有统计学差异。结论 5-HTTLPR与PSD及UD均无显著关联,S/S基因型患者可能抑郁症状较重,12周治疗后携带S/S基因型和S等位基因患者的临床痊愈率较低。     

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.     

5-HTTLPR,anxiety and gender interaction moderates right amygdala volume in healthy subjects

Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into ‘no anxiety’ and ‘subclinical anxiety’ groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours.     

Influence of 5-HTTLPR polymorphism on resting state perfusion in patients with major depression

Neuroimaging studies in major depressive disorder (MDD) have indicated dysregulation in a network involving prefrontal cortex, subgenual cingulate and the amygdalae, which is known to be modulated by serotonin. The serotonergic system is the principal target for pharmacological treatment in MDD and the functional variable serotonin promoter polymorphism (5-HTTLPR) influences susceptibility, course and treatment response of MDD. Using data from a previously published sample of 89 MDD-patients, we examined post hoc the effect of 5-HTTLPR status on resting state perfusion, as measured with ^99mTc-HMPAO-SPECT. MDD patients were stratified according to receptor polymorphism, both using a bi-allelic (group A: L/L vs. group B: S/S and S/L genotype) and a tri-allelic approach (Group A′: LA/LA vs. Group B′: non-LA/LA genotype). There were no significant differences between both subgroups regarding age, gender, severity of depression, medication, or treatment response (p > 0.1). Using the bi-allelic approach, Group B, compared to group A, revealed a significantly higher resting state perfusion in medial prefrontal cortex (p_voxel (FWE) < 0.05). Additional ROI analyses showed relative overactivity of the amygdalae in group B (p_voxel (FWE) < 0.05). Similar effects were observed in the tri-allelic approach. The opposite contrasts (Group A > Group B) revealed no significant effects. We demonstrate that in patients with MDD, 5-HTTLPR gene polymorphism modulates resting state perfusion in key structures of mood processing. While the clinical impact of these findings will need to be further investigated in larger cohort studies, the necessity to monitor and to account for individual 5-HTTLPR-status in future MDD imaging studies is highly recommended.     

Negative emotionality mediates the association of 5-HTTLPR genotype and depression in children with and without ADHD

The 44-base-pair polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been implicated in the etiology of depression, but relatively little is known about potential mediators of this association. Although dimensions of temperament are likely to be proximal to the neurobiological and genetic factors underlying depression, studies have yet to formally evaluate temperament as a potential causal pathway. We examined individual differences in dimensions of temperament [negative emotionality (NE), prosociality (PRO), and daring (DA)] as potential mediators of 5-HTTLPR genotype and child depression. Using a multiple mediation framework, we tested the association of child 5-HTTLPR genotype and these dimensions of temperament with multi-informant ratings of child depression in a sample of 218 children with and without attention-deficit/hyperactivity disorder (ADHD). The long allele of 5-HTTLPR was associated with higher NE and lower PRO, but not DA. High NE mediated the association of 5-HTTLPR genotype and separate parent and teacher ratings of depression. ADHD status did not moderate the mediational role of NE for 5-HTTLPR and depression. Results suggest that NE may constitute a pathway between 5-HTTLPR and child depression. The role of genetic variation and temperament dimensions as intermediate traits in the development of depression is discussed.     

The selective serotonin re-uptake inhibitor escitalopram modulates the panic response to cholecystokinin tetrapeptide in healthy men depending on 5-HTTLPR genotype

Selective serotonin re-uptake inhibitors, such as escitalopram, are currently the treatment of choice for patients with panic disorder. The panic response to intravenous cholecystokinin tetrapeptide, a potentially useful paradigm for volunteer translational studies, has so far not been investigated in healthy man after respective pre-treatment. In a double-blind, placebo-controlled, randomized, within subject cross-over design 30 healthy young men, 15 each with the long/long or short/short genotype for the serotonin transporter linked polymorphic region, were pre-treated with 10 mg/d of escitalopram orally for six weeks and then challenged with 50 μg of cholecystokinin tetrapeptide. The primary outcome measure was the increase of Acute Panic Inventory ratings by cholecystokinin tetrapeptide. The increase of anxiety, tension and stress hormone secretion were secondary outcome measures. A significant treatment by genotype effect on the increases of Acute Panic Inventory ratings ermerged. Panic induced by cholecystokinin tetrapeptide was significantly more pronounced in the short/short genotype subjects under escitalopram vs. placebo pre-treatment. With the exception of significantly elevated serum prolactin after escitalopram, no effects in the secondary outcome measures were detected. Contrary to our expectation, no inhibitory effect of escitalopram upon panic symptoms elicited by choleystokinin tetrapeptide could be demonstrated in healthy men. These findings do not support the potential usefulness of this panic model for proof-of-concept studies. The biological underpinnings of the increased panic symptoms after escitalopram in our volunteers with short/short genotype need further research.     

Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

Objective

We investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression.

Methods

Final analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed.

Results

The 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing.

Conclusion

This result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary.     

Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults

Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations among depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes.     

The long rather than the short allele of 5-HTTLPR predisposes Han Chinese to anxiety and reduced connectivity between prefrontal cortex and amygdala

The short allele of the serotonin-transporter gene is associated with higher risk for anxiety and depression in Caucasians, but this association is still unclear in Asians. Here, we addressed this issue using behavioral and multi-modal MRI approaches in a large group of healthy Han Chinese participants (n = 233). In contrast to findings in Caucasians, we found that long-allele (L) carriers had higher anxiety scores. In another group (n = 64) experiencing significant levels of depression or anxiety, the L-allele frequency was also significantly higher. In healthy participants, L-carriers had reduced functional and anatomical connectivity between the amygdala and prefrontal cortex (PFC), which was correlated with anxiety or depression scores. Our findings demonstrated that in Chinese Han participants, in contrast to Caucasians, the L-allele confers vulnerability to anxiety or depression and weakens top-down emotional control between the PFC and amygdala. Therefore, ethnic background should be taken into account in gene-related studies and their potential clinical applications.     

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.     

5-HTTLPR moderates the association between attention away from angry faces and prospective depression among youth

Attention bias to emotion has been studied as a risk factor associated with depression. No study has examined whether attention bias within the context of measured genetic risk leads to increased risk for clinical depressive episodes over time. The current study investigated whether genetic risk, as indexed by the serotonin-transporter-linked polymorphic region (5-HTTLPR), moderated the relationship between attention bias to emotional faces and clinical depression onset prospectively across 18-months in a community sample of youth (n = 428; mean age = 11.97, SD = 2.28; 59% girls). Youth who attended away from angry emotional faces and were homozygous for the S allele of the 5-HTTLPR polymorphism were at greater risk for prospective depressive episode onset. The current study's findings highlight the importance of examining risk for depression across multiple levels of analysis and demonstrate attention away from threat as a possible point of intervention related to attention bias modification and depression treatment among youth.     

Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events

Fear learning is a crucial process in the pathogeneses of psychiatric disorders, which highlights the need to identify specific factors contributing to interindividual variation. We hypothesized variation in the serotonin transporter gene (5-HTTLPR) and stressful life events (SLEs) to be associated with neural correlates of fear conditioning in a sample of healthy male adults (n = 47). Subjects were exposed to a differential fear conditioning paradigm after being preselected regarding 5-HTTLPR genotype and SLEs. Individual differences in brain activity as measured by functional magnetic resonance imaging (fMRI), skin conductance responses and preference ratings were assessed. We report significant variation in neural correlates of fear conditioning as a function of 5-HTTLPR genotype. Specifically, the conditioned stimulus (CS⁺) elicited elevated activity within the fear-network (amygdala, insula, thalamus, occipital cortex) in subjects carrying two copies of the 5-HTTLPR S′ allele. Moreover, our results revealed preliminary evidence for a significant gene-by-environment interaction, such as homozygous carriers of the 5-HTTLPR S′ allele with a history of SLEs demonstrated elevated reactivity to the CS⁺ in the occipital cortex and the insula. Our findings contribute to the current debate on 5-HTTLPR x SLEs interaction by investigating crucial alterations on an intermediate phenotype level which may convey an elevated vulnerability for the development of psychopathology.     

Sexual dysfunction during treatment with serotonergic and noradrenergic antidepressants: Clinical description and the role of the 5-HTTLPR

Abstract

Objectives. Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant). Methods. A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery–Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the Sexual Functioning Questionnaire. Results. The incidence of reported SD after 12 weeks of treatment was relatively low, and did not differ significantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no significant interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR. Conclusions. In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no apparent effect of the 5-HTTLPR on the observed decline in SD.