Towards a genetically validated new affective temperament scale: a delineation of the temperament phenotype of 5-HTTLPR using the TEMPS-A

BackgroundAlthough it has been described that affective temperaments are associated with the 5-HTTLPR, less attention was paid to the association between this polymorphism and subscales and items related to each affective temperament. The aim of our study was to investigate the association of affective temperament subscales and individual items with the s allele of the 5-HTTLPR.Method138 psychiatrically healthy women completed the TEMPS-A questionnaire and were genotyped for 5-HTTLPR. Scores of subjects on the temperament scales, subscales and items in the three genotype and the two phenotype groups were compared using ANOVA. We selected items with significantly different mean scores between the three genotype groups and the two phenotype groups separately and performed item analysis.ResultsSubjects in the different 5-HTTLPR genotype and phenotype groups have significantly different score on scales measuring depressive, cyclothymic, irritable and anxious temperaments, and several subscales composing these temperamental scales. Subjects in the three genotype groups scored significantly different on 11 items, 8 of these remained in a derived genotype scale after item analysis. Subjects in the two phenotype groups had significantly different scores on 12 items, 9 of them were retained in a derived phenotype scale after item analysis.LimitationsOur sample was relatively small and included only women.ConclusionsOur data provide support for the association of affective temperaments with the s allele. Although the cyclothymic temperament shows the strongest association, all temperaments within the depressive superfactor have a similar share in this association. The newly derived 5-HTTLPR Phenotype Scale shows strong association with 5-HTTLPR genotype and phenotype, therefore this scale should be further investigated in relation to psychiatric disorders, as well as psychological traits and temperaments.     

The serotonin transporter promoter repeat length polymorphism,seasonal affective disorder and seasonality

BACKGROUND: Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD. METHOD: One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets. RESULTS: No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N = 298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set. CONCLUSIONS: These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.     

Neural and behavioral responses to threatening emotion faces in children as a function of the short allele of the serotonin transporter gene

Recent evidence suggests that a genetic polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) mediates stress reactivity in adults. Little is known, however, about this gene-brain association in childhood and adolescence, generally conceptualized as a time of heightened stress reactivity. The present study examines the association between 5-HTTLPR allelic variation and responses to fearful and angry faces presented both sub- and supraliminally in participants, ages 9-17. Behaviorally, carriers of the 5-HTTLPR short (s) allele exhibited significantly greater attentional bias to subliminally presented fear faces than did their long (l)-allele homozygous counterparts. Moreover, s-allele carriers showed greater neural activations to fearful and angry faces than did l-allele homozygotes in various regions of association cortex previously linked to attention control in adults. These results indicate that in children and adolescents, s-allele carriers can be distinguished from l-allele homozygotes on the basis of hypervigilant behavioral and neural processing of negative material.     

Early-emerging cognitive vulnerability to depression and the serotonin transporter promoter region polymorphism

BACKGROUND: Serotonin transporter promoter (5-HTTLPR) genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing. LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the "stress-sensitivity" conferred by this genotype.     

Serotonin transporter promoter region (5-HTTLPR) polymorphism predicts resting respiratory sinus arrhythmia

Respiratory sinus arrhythmia (RSA) is often conceptualized as an index of physiological flexibility that has been related to emotion regulatory capacity. Although behavioral genetics research indicates that RSA is partly heritable, relatively few molecular genetics studies have been conducted. We examined whether the serotonin transporter promoter region (5-HTTLPR) polymorphism was associated with resting RSA among healthy young adults (N=71). Short 5-HTTLPR allele carriers had significantly lower resting RSA than long 5-HTTLPR homozygotes. Genotype explained 5% of the variance in resting RSA. Although firm conclusions depend on further study, the short allele of the 5-HTTLPR polymorphism may contribute to individual differences in RSA and its behavioral correlates.     

Temporal recalibration to tactile-visual asynchronous stimuli

Repetitive transcranial magnetic stimulation (rTMS) is a painless and safe brain stimulation technique that has been found to be effective in treating depression symptoms. The potential usefulness of rTMS, in particular to treat drug resistant patients, might be increased by identifying genetic predictors of efficacy. According to this rationale, we investigated the role of two functional polymorphisms in the genes coding for the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF Val66Met), and rTMS response in a group of 36 drug resistant patients affected by mood disorders. rTMS treatment significantly improved depression symptomatology (p < 0.0001) and the response was significantly greater in 5-HTTLPR LL homozygotes compared to S allele carriers (p = 0.007) and in BDNF Val/Val homozygotes compared to Met allele carriers (p = 0.024). These findings provide evidences about the involvement of both polymorphisms in rTMS antidepressant response. Further investigations in larger samples are needed to clarify the usefulness of 5-HTTLPR and BDNF Val66Met genotyping in the optimization of non-pharmacological treatments in mood disorders.     

Parental Serotonin Transporter Polymorphism (5-HTTLPR) Moderates Associations of Stress and Child Behavior With Parenting Behavior

The serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with caregiving in nonhuman animals and with affective and cognitive correlates of human parenting, yet its association with human parenting is largely unknown. Using a well-characterized sample of parents and offspring, we evaluated the association of parental 5-HTTLPR with observed positive and negative parenting behavior, as well as its biologically plausible moderation of child-related stress and disruptive child behavior as predictors of parenting. One hundred and sixty-two parents (86% mothers) and their 6- to 9-year-old children with and without attention-deficit/hyperactivity disorder were ascertained using multiple methods including structured interviews, rating scales, and observed parent-child interaction, yielding strong measures of key constructs. Controlling for multiple youth-level (e.g., sex, 5-HTTLPR genotype, disruptive behavior) and parent-level (e.g., demographics, depression, attention-deficit/hyperactivity disorder) factors, parents with an S allele exhibited significantly less observed positive parenting than those with the LL genotype. Significant Gene × Environment interactions were also observed: Child-related stress was negatively associated with observed parental negativity among SS/SL genotype parents but not LL genotype parents; next, observed disruptive child behavior was positively associated with parental negativity for both genotypes, but the effect was strongest in SS/SL parents. These preliminary findings suggest that parental 5-HTTLPR is uniquely associated with positive and negative parenting behavior, with more specific patterns according to child-related stress and disruptive child behavior. We consider implications for future research evaluating genetic influences on parenting as well as considerations for designing and delivering parenting-based interventions.     

Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces

Both attention biases to threat and a serotonin-transporter gene polymorphism (5-HTTLPR) have been linked to heightened neural activation to threat and the emergence of anxiety. The short allele of 5-HTTLPR may act via its effect on neurotransmitter availability, while attention biases shape broad patterns of cognitive processing. We examined individual differences in attention bias to emotion faces as a function of 5-HTTLPR genotype. Adolescents (N = 117) were classified for presumed SLC6A4 expression based on 5-HTTLPR—low (SS, SL_G, or L_GL_G), intermediate (SL_A or L_AL_G), or high (L_AL_A). Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotype-predicted neurotransmission levels (low > intermediate > high). The reverse pattern was evident for happy faces. The data indicate a linear relation between 5-HTTLPR allelic status and attention biases to emotion, demonstrating a genetic mechanism for biased attention using ecologically valid stimuli that target socioemotional adaptation.     

The temporal dynamics of cognitive reappraisal: Cardiovascular consequences of downregulation of negative emotion and upregulation of positive emotion

This study examines the effects of cognitive reappraisal on the cardiovascular response to affective stimuli. Participants (N = 53) were shown affective images and were asked either to attend to the images, or to downregulate negative affect through reappraisal of negative images or upregulate positive affect through reappraisal of positive images while continuous measures of cardiovascular activity were recorded. Reappraisal of negative images was associated with lower total peripheral resistance and larger cardiac output in the prestimulus period, whereas reappraisal of positive images was associated with less pronounced decreases of heart rate, cardiac output, and mean blood pressure in the viewing period as compared to unregulated conditions. The results indicate that cognitive reappraisal engenders adaptive hemodynamic profiles both during anticipation and during viewing of affective images depending on their valence and the regulatory goal.     

Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism,Anxiety and Depression

We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P < 0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression. Edited by Stacey Cherny     

Personality and the serotonin transporter gene: Associations in a longitudinal population-based study

Associations between the promoter polymorphism of the serotonin transporter gene (5-HTTLPR) and anxiety-related personality traits in healthy adult subjects have been inconsistent. We assessed personality in participants of the Estonian Children Personality Behaviour and Health Study, using parental reports and self-reports. In the younger cohort, according to parental assessments at ages 9 and 15, children homozygous for the S allele had significantly higher scores of Neuroticism and lower scores of Openness, Agreeableness and Conscientiousness. Parental assessment of the older cohort at ages 15 and 18 did not yield any genotype effect on personality; however, interaction of cohort and genotype was not significant. According to self-reports, SS homozygotes had higher Neuroticism at age 15 but not at age 18. Thus, homozygocity for the S allele of the 5-HTTLPR is related to anxiety-related personality traits in general population, but this is easier to detect before adolescence.     

Facilitating actions of an AMPA receptor potentiator upon extinction of contextually conditioned fear response in stressed mice

Mounting evidence supports the association between a polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) and suicidal behaviour. Recently, a novel variant of the 5-HTTLPR L allele was identified. The previously unknown L_G allele produced similar levels of gene expression to the S allele and might have been misclassified as a “high-expression” allele in previous association studies. In this study, we aimed to compare the genotype distribution of the tri-allelic 5-HTTLPR polymorphism in 168 Chinese patients with schizophrenia, including 60 suicide attempters and 108 non-suicide attempters. In our analysis, which used the L_A dominant model, it was found that the L_A allele carriers were significantly more likely to have attempted suicide (p = 0.035). Further analysis showed this association existed only in male patients (p = 0.012). A similar association between the L_A allele and violent suicide attempt was also found (p = 0.028). In addition, logistic regression confirmed our findings that male L_A allele carriers were at a higher risk of suicide, although the lack of a significant association in females may reflect insufficient power due to small sample size. However, no association was found when we examined the traditional bi-allelic 5-HTTLPR. These findings differ from those reported in Caucasian subjects, where no associations have been reported. Different genetic backgrounds may give rise to different allelic distribution, causing differential effects on the expression of endophenotypes of suicide behaviours. Although the potential influence of multiple comparisons might weaken our findings, our study provides preliminary evidence for a potentially gender-specific role of a “high-expression” 5-HTTLPR polymorphism in susceptibility to suicide in Chinese patients with schizophrenia.     

Increased neural sensitivity to self‐relevant stimuli in major depressive disorder

The current research examined how individuals with depression process emotional, self‐relevant stimuli. Across two studies, individuals with depression and healthy controls read stimuli that varied in self‐relevance while EEG data were recorded. We examined the late positive potential (LPP), an ERP component that captures the dynamic allocation of attention to motivationally salient stimuli. In Study 1, participants read single words in a passive‐viewing task. Participants viewed negative, positive, or neutral words that were either normative or self‐generated. Exploratory analyses indicated that participants with depression exhibited affective modulation of the LPP for self‐generated stimuli only (both positive and negative) and not for normative stimuli; healthy controls exhibited similar affective modulation of the LPP for both self‐relevant and normative stimuli. In Study 2, using a separate sample and a different task, stimuli were provided within the context of sentence stems referring to the self or other people. Participants with depression were more likely to endorse negative self‐referent sentences and reject positive ones compared to healthy controls. Depressed participants also exhibited an increased LPP to negative stimuli compared to positive or neutral stimuli. Together, these two studies suggest that depression is characterized by relatively increased sensitivity to affective self‐relevant stimuli, perhaps in the context of a broader reduction in emotional reactivity to stimuli that are not self‐relevant. Thus, depression may be characterized by a more nuanced pattern based on the degree of stimulus self‐relevance than either a global decrease or increase in reactivity to affective stimuli.     

Emotional reactivity and regulation in individuals with psychopathic traits: Evidence for a disconnect between neurophysiology and self‐report

Individuals with psychopathic traits often demonstrate blunted reactivity to negative emotional stimuli. However, it is not yet clear whether these individuals also have difficulty regulating their emotional responses to negative stimuli. To address this question, participants with varying levels of psychopathic traits (indexed by the Triarchic Measure of Psychopathy; Patrick, 2010) completed a task in which they passively viewed, increased, or decreased their emotions to negative picture stimuli while electrocortical activity was recorded. During passive viewing of negative images, higher boldness, but not higher disinhibition or meanness, was associated with reduced amplitude of the late positive potential (LPP), an ERP that indexes reactivity to emotionally relevant stimuli. However, all participants demonstrated expected enhancement of the LPP when asked to increase their emotional response. Participants did not show expected suppression of the LPP when asked to decrease their emotional response. Contrary to the electrophysiological data, individuals with higher boldness did not self‐report experiencing blunted emotional response during passive viewing trials, and they reported experiencing greater emotional reactivity relative to other participants when regulating (e.g., both increasing and decreasing) their emotions. Results suggest inconsistency between physiological and self‐report indices of emotion among high‐bold individuals during both affective processing and regulation.     

Family-based association study of the serotonin transporter gene polymorphisms in Korean ADHD trios.

The dopamine (DA) system has been implicated in attention deficit hyperactivity disorder (ADHD) based on pharmacologic evidence. Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene. Two common polymorphisms, 5-HTTLPR and the intron 2 VNTR, have been studied for association in ADHD, with both positive (increased frequency of long allele of 5-HTTLPR and decreased frequency of 12 repeats of the intron 2 VNTR) and negative findings. However, there has not been an association study in an East Asian ADHD population. In this study, we examined the genotypes of these two polymorphisms in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity-impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5-HTTLPR and ADHD (chi2 = 4.9, P = 0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P = 0.031), but case-control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association. This result suggests that future studies should include more polymorphic markers and subjects to thoroughly investigate a potential association between SLC6A4 and ADHD in the Korean population.     

Early impact of 5-HTTLPR polymorphism on the neural correlates of sadness

Healthy adults carrying the short (S) allele of the human serotonin transporter gene linked polymorphism (5-HTTLPR) show increased amygdala activation during visual processing of emotionally negative stimuli compared to healthy adults homozygous for the long (L) allele. To determine whether abnormal brain responses during negative emotion appear early in life in S allele carriers, functional magnetic resonance imaging (fMRI) was used to measure brain activity during a transient state of sadness in children carrying the S allele (S group) or homozygous for the L allele (L group). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and sad film excerpts. During the sad condition (relative to the neutral condition), there was significantly greater activation in the S group compared to the L group in brain regions known to be involved in normal sadness and major depression. Given that the 5-HTTLPR polymorphism has been associated with mood disorders, it is plausible that the abnormal pattern of regional brain activity detected here, in children carrying the S allele, increases susceptibility to emotional dysregulation and depressive symptoms.     

The 5-HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent

Covault et al. [Covault et al. (2007); Biol Psychiatry 61(5): 609-616] reported that the common functional polymorphism, 5-HTTLPR, in the serotonin transporter gene moderated the association between past-year stressful events and daily reports of drinking in a sample of European-American (EA) college students. We examined this effect in college students of African descent. Students recruited at a Historically Black University (n = 564) completed web-based measures of past-year stressful life experiences and daily reports of drinking and heavy drinking over a 30-day period. Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism and dichotomized as low-activity S' allele carriers or high-activity L' homozygotes. Generalized linear models were used to examine the effects of life stress, genotype, and their interaction on the two drinking measures. In students who completed 15 or more daily surveys (n = 393), there was a significant interaction of past-year stressful events, 5-HTTLPR genotype, and gender on the number of drinking days (P = 0.002). Similar findings were obtained in relation to heavy drinking days (P = 0.007). Men showed a main effect of past-year stressful events on both drinking outcomes (P's < 0.001), but no main or moderator effects of genotype. In women, the S' allele moderated the impact of past-year life stressors on the frequency of drinking and heavy drinking days (P's < 0.001). In college students of African descent, past-year stressful events were associated with more frequent drinking and heavy drinking, an effect that was moderated by the 5-HTTLPR polymorphism. However, in contrast to the findings in EA students, in the current sample, 5-HTTLPR moderated the association only among women.     

The serotonin transporter gene linked polymorphic region is associated with the behavioral response to repeated stress exposure in infant rhesus macaques

The short allele of the serotonin transporter linked polymorphic region (5-HTTLPR) moderates the effects of stress on vulnerability to mood and anxiety disorders. The mechanism by which this occurs may relate to differential sensitivity to stressful life events. Here we explored whether 5-HTTLPR and sex affected behavioral responses to repeated maternal separation in infant rhesus macaques. Behaviors were collected during the acute (Day 1) and the chronic (Days 2-4) phases of the separation, and the effects of duration of separation (acute vs. chronic), genotype (long/long vs. short allele), and sex (male vs. female) on behavioral responses were analyzed across four successive separations. Males increased their levels of locomotion with repeated maternal separation, whereas females exhibited an increase in frequency of self-directed behavior, a measure of "depression-like" behavior. The short-allele predicted increased environmental exploration, particularly during the chronic phase of social separation, indicative of higher arousal. In addition, the short-allele carriers were more likely to increase their levels of self-directed behavior during the chronic phase of separation, as a function of repeated exposures. These findings suggest that the short allele may increase reactivity to repeated, chronic stressors, leaving them more vulnerable to affective psychopathology, with females particularly vulnerable.     

Coaction of stress and serotonin transporter genotype in predicting aggression at the transition to adulthood

Despite consistent evidence that serotonin functioning affects stress reactivity and vulnerability to aggression, research on serotonin gene-stress interactions (G × E) in the development of aggression remains limited. The present study investigated variation in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress-aggression association at the transition to adulthood. Multiple informants and multiple measures were used to assess aggression in a cohort of 381 Australian youth (61% female, 93% Caucasian) interviewed at ages 15 and 20. At age 20, semistructured interviews assessed acute and chronic stressors occurring in the past 12 months. Structural equation modeling analyses revealed a significant main effect of chronic stress, but not 5-HTTLPR or acute stress, on increases in aggression at age 20. Consistent with G × E hypotheses, 5-HTTLPR short allele carriers demonstrated greater increments in aggression following chronic stress relative to long allele homozygotes. The strength of chronic stress G × E did not vary according to sex. Variation at 5-HTTLPR appears to contribute to individual differences in aggressive reactions to chronic stress at the transition to adulthood.     

The immune system and happiness

Human ability to experience negative and positive emotions has an evolutionary perspective and the presence of feelings designed to influence behavior should thus be reflected in physiological and immune interactions. The complex interactions between the immune system and the central nervous system have been studied extensively in schizophrenia and depression. On the other hand, effects of positive human emotions, especially happiness, on physiological parameters and immunity have received very little attention. Emotions are intimately involved in the initiation or progression of cancer, HIV, cardiovascular disease, and autoimmune disorders. The specific physiological responses induced by pleasant stimuli were recently investigated with the immune and endocrine systems being monitored when pleasant stimuli such as odors and emotional pictures were presented to subjects. The results revealed that an increase in secretory immunoglobulin A and a decrease in salivary cortisol were induced by pleasant emotions. The mechanisms by which positive as opposed to negative states are instantiated in the brain and interact with the immune system are not yet understood. The present review investigates relations among physiological measures of affective style, psychological well-being, and immune function. There is data to support the hypothesis that individuals characterized by a more negative affective style poorly recruit their immune response and may be at risk for illness more so than those with a positive affective style. Future research is needed to expand our knowledge of the physiological and immune interactions of positive emotional states and their beneficial effects on health.