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.     

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.     

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.     

Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children.

BACKGROUND: Child abuse and genotype interact to contribute to risk for depression in children. This study examined gene-by-gene and gene-by-environment interactions. METHODS: The study included 196 children: 109 maltreated and 87 nonmaltreated comparison subjects. Measures of psychiatric symptomatology and social supports were obtained using standard research instruments, and serotonin transporter (5-HTTLPR) (locus SLC6A4) and brain-derived neurotrophic factor (BDNF) (variant val66met) genotypes were obtained from saliva-derived DNA specimens. Population structure was controlled by means of ancestral proportion scores computed based on genotypes of ancestry informative markers in the entire sample. RESULTS: There was a significant three-way interaction between BDNF genotype, 5-HTTLPR, and maltreatment history in predicting depression. Children with the met allele of the BDNF gene and two short alleles of 5-HTTLPR had the highest depression scores, but the vulnerability associated with these two genotypes was only evident in the maltreated children. A significant four-way interaction also emerged, with social supports found to further moderate risk for depression. CONCLUSIONS: To the best of our knowledge, this is the first investigation to demonstrate a gene-by-gene interaction conveying vulnerability to depression. The current data also show a protective effect of social supports in ameliorating genetic and environmental risk for psychopathology.     

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.     

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.     

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。     

Seasonal variation of serotonin turnover in human cerebrospinal fluid,depressive symptoms and the role of the 5-HTTLPR

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10⁻⁷) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman''s rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.     

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 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.     

Association of the s allele of the 5-HTTLPR with neuroticism-related traits and temperaments in a psychiatrically healthy population

Introduction  Research concerning the genetic background of traits, temperaments and psychiatric disorders has been rapidly expanding. One of the most frequently studied genetic polymorphisms in the background of psychological and psychiatric phenomena is the 5-HTTLPR polymorphism of the serotonin transporter gene which has earlier been found to be associated with neuroticism and neuroticism-related traits and disorders. However, both the neuroticism trait and psychiatric disorders are complex and composed of several subfacets. The aim of our study was to investigate the association of the 5-HTTLPR polymorphism with several smaller, distinct and better characterisable phenomena related to the neuroticism trait. Methods  169 healthy females participated in the study. All participants completed the Buss–Durkee Hostility Inventory (BDHI), the State-Trait Anxiety Inventory (STAI), The Zung Self-rating Depression Scale (ZSDS), the Beck Hopelessness Scale, the SCL-51, the Temperament and Character Inventory (TCI) and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) questionnaire. All subjects were genotyped for the 5-HTTLPR using PCR. Data were analysed with ANOVA and MANCOVA with age as a covariate. Results  We found that the presence of the s allele was significantly associated with anxiety, depression, hopelessness, guilt, hostility, aggression, presence of neurotic symptoms, self-directedness and affective temperaments carrying a depressive component even when controlling for age. Conclusions  Our study is the first that confirms that traits and characteristics related to neuroticism, such as increased anxiety, depression, hopelessness, somatization, feeling of guilt, hostility, aggression, lack of self-directedness and affective temperament are consistently and independently associated with the 5-HTTLPR polymorphism of the serotonin transporter gene. Our study therefore suggests that neuroticism can be considered a unified construct not only from a phenotypical but also from a genetic point of view and 5HTTLPR can be considered one component of its polygenic background. Our results thus yield further insight into the role of the 5-HTTLPR in the background of neuroticism and neuroticism-related psychiatric disorders.     

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.     

The 5-HTTLPR Polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder

Background

Impulsivity belongs to the key features of Borderline Personality Disorder (BPD). It has been linked to altered serotoninergic neurotransmission and, genetically, to an over-representation of the short (S) allele of the serotonin transporter promoter-linked polymorphic region polymorphism (5-HTTLPR). On the other hand, serious life events (SLE) are of major importance in the development of BPD. However, the inter-relations between SLEs, impulsivity, and 5-HTTLPR are not understood.

Method

159 BPD patients from Germany were included in this study. Impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). We analysed (1) the effects of SLEs on impulsivity; and (2) modulating effects of the 5-HTTLPR polymorphism on the effects of SLEs on impulsivity.

Results

Regression analyses confirmed a decreasing effect of childhood sexual abuse, the cumulative SLE-related reactions and the impairment by SLEs on BIS sum score. Regarding BIS sum score, all SLEs except for rape were associated with a decrease of impulsivity in SS/SL carriers and an increase of BIS sum score in LL carriers.

Conclusions

This study analyzing a specific gene x environment interaction in BPD patients suggests an interaction between SLEs and the 5-HTTLPR S/L polymorphism in the development of impulsivity in BPD patients. Clinical and research implications are discussed.     

The influence of 5-HTTLPR transporter genotype on amygdala-subgenual anterior cingulate cortex connectivity in autism spectrum disorder

Social deficits in autism spectrum disorder (ASD) are linked to amygdala functioning and functional connection between the amygdala and subgenual anterior cingulate cortex (sACC) is involved in the modulation of amygdala activity. Impairments in behavioral symptoms and amygdala activation and connectivity with the sACC seem to vary by serotonin transporter-linked polymorphic region (5-HTTLPR) variant genotype in diverse populations. The current preliminary investigation examines whether amygdala-sACC connectivity differs by 5-HTTLPR genotype and relates to social functioning in ASD. A sample of 108 children and adolescents (44 ASD) completed an fMRI face-processing task. Youth with ASD and low expressing 5-HTTLPR genotypes showed significantly greater connectivity than youth with ASD and higher expressing genotypes as well as typically developing (TD) individuals with both low and higher expressing genotypes, in the comparison of happy vs. baseline faces and happy vs. neutral faces. Moreover, individuals with ASD and higher expressing genotypes exhibit a negative relationship between amygdala-sACC connectivity and social dysfunction. Altered amygdala-sACC coupling based on 5-HTTLPR genotype may help explain some of the heterogeneity in neural and social function observed in ASD. This is the first ASD study to combine genetic polymorphism analyses and functional connectivity in the context of a social task.     

Afraid to help: Social anxiety partially mediates the association between 5-HTTLPR triallelic genotype and prosocial behavior

There is growing evidence that the serotonin system influences prosocial behavior. We examined whether anxiety mediated the association between variation in the serotonin transporter gene regulatory region (5-HTTLPR) and prosocial behavior. We collected self-reported tendencies to avoid certain situations and history of helping others using standard instruments and buccal cells for standard 5-HTTLPR genotyping from 398 undergraduate students. Triallelic 5-HTTLPR genotype was significantly associated with prosocial behavior and the effect was partially mediated by social anxiety, such that those carrying the S′ allele reported higher levels of social avoidance and lower rates of helping others. These results are consistent with accounts of the role of serotonin on anxiety and prosocial behavior and suggest that targeted efforts to reduce social anxiety in S′ allele carriers may enhance prosocial behavior.     

Comorbid anxiety and depression in school-aged children with attention deficit hyperactivity disorder (ADHD) and selfreported symptoms of ADHD,anxiety, and depression among parents of school-aged children with and without ADHD

Background

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children that can extend into adulthood and that is often associated with a variety of comorbid psychiatric disorders.

Aim

Assess the comorbidity of ADHD with anxiety disorders and depressive disorders in school-aged children, and the relationship of the severity of ADHD, anxiety, and depressive symptoms in children who have ADHD with the severity of the corresponding symptoms in their parents.

Methods

A two-stage screening process identified children 7-10 years of age with and without ADHD treated at the Xin Hua Hospital in Shanghai. ADHD and other DSM-IV diagnoses were determined by a senior clinician using the Schedule for Affective Disorder and Schizophrenia for School-Aged Children (K-SADS-PL). One parent for each enrolled child completed three self-report scales: the ADHD Adult Self Report Scale (ASRS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI). In total 135 children with ADHD and 65 control group children without ADHD were enrolled; parents for 94 of the children with ADHD and 63 of the children without ADHD completed the parental assessment scales.

Results

Among the 135 children with ADHD, 27% had a comorbid anxiety disorder, 18% had a comorbid depressive disorder, and another 15% had both comorbid anxiety and depressive disorders. Parents of children with ADHD self-reported more severe ADHD inattention symptoms than parents of children without ADHD and were more likely to meet criteria for adult ADHD. Mothers (but not fathers) of children with ADHD had significantly more severe trait anxiety and depressive symptoms than mothers of children without ADHD. Among children with ADHD, the severity of ADHD symptoms was not significantly correlated with the severity of ADHD symptoms in parents, but depressive symptoms and anxiety symptoms in the children were significantly correlated with the corresponding symptoms in the parents.

Conclusion

School-aged children with ADHD commonly suffer from comorbid anxiety and depressive disorders, and the severity of these symptoms parallels the level of anxiety and depressive symptoms in their parents. Self-reported symptoms of ADHD are significantly more common in parents of children with ADHD than in parents of children without ADHD. Longitudinal studies are needed to disentangle the genetic, biological, and social factors responsible for these complex inter-relationships.