Serotonin transporter gene polymorphism (5-HTTLPR) L allele interacts with stress to increase anxiety symptoms in Chinese adolescents: a multiwave longitudinal study.
ABSTRACT: Previous studies of the interaction between a functional polymorphism in the serotonin transporter gene-linked promoter region (5-HTTLPR) and stress in anxiety-related phenotypes have produced inconsistent results. The aim of the current study was to examine the effect of the 5-HTTLPR?×?stress interaction on anxiety symptoms in Chinese adolescents.A total of 651 healthy adolescents [323 females and 328 males; age 14-17 (mean = 16.27, standard deviation = 0.77)] participated in this study. At the initial assessment, participants completed self-report measures assessing anxiety symptoms, depressive symptoms and stressful life events. Additionally, anxiety symptoms and stressful life events were assessed once every 3 months for the subsequent 9 months. A hierarchical linear model (HLM) was used to investigate the 5-HTTLPR?×?stress interaction.The HLM indicated no main effect of 5-HTTLPR on anxiety symptoms. Significant 5-HTTLPR?×?stress interaction effect in predicting anxiety symptoms was found. Specifically, individuals with the 5-HTTLPR L allele exhibited more anxiety symptoms related to stressful life events.The association between stress and anxiety symptoms is moderated by 5-HTTLPR. The 5-HTTLPR L allele increases individuals' vulnerability to anxiety under stress situations.
Project description:Associations between stressful life events (SLEs) and internalizing psychopathology are complex and bidirectional, involving interactions among stressors across development to predict psychopathology (i.e., stress sensitization) and psychopathology predicting greater exposure to SLEs (i.e., stress generation). Although stress sensitization and generation theoretical models inherently focus on within-person effects, most previous research has compared average levels of stress and psychopathology across individuals in a sample (i.e., between-person effects). The present study addressed this gap by investigating stress sensitization and stress generation effects in a multiwave, prospective study of SLEs and adolescent depression and anxiety symptoms. Depression, anxiety, and SLE exposure were assessed every 3 months for 2 years (8 waves of data) in a sample of adolescents (n = 382, aged 11 to 15 at baseline). Multilevel modeling revealed within-person stress sensitization effects such that the association between within-person increases in SLEs and depression, but not anxiety, symptoms were stronger among adolescents who experienced higher average levels of SLEs across 2 years. We also observed within-person stress generation effects, such that adolescents reported a greater number of dependent-interpersonal SLEs during time periods after experiencing higher levels of depression at the previous wave than was typical for them. Although no within-person stress generation effects emerged for anxiety, higher overall levels of anxiety predicted greater exposure to dependent-interpersonal SLEs. Our findings extend prior work by demonstrating stress sensitization in predicting depression following normative forms of SLEs and stress generation effects for both depression and anxiety using a multilevel modeling approach. Clinical implications include an individualized approach to interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Project description:Caspi et al. (2003) found an interaction between the serotonin transporter polymorphism gene (5-HTTLPR) and stressful life events on depression. Subsequent attempts to replicate have been inconsistent. The present research included long allele variants modified by SNP rs25531 and tested the interaction on adolescents' trajectories of anxious/depressed symptoms, with consideration of possible age effects. Adolescents (N = 574), of whom 436 were genotyped, were followed from ages 12 to 17. Analyses demonstrated a G × E interaction in predicting the development of anxious/depressed symptoms. Specifically, adolescents with lower serotonin transcriptional efficiency (TE) genotypes whose mothers reported more stressful events were reported to show more anxious/depressed symptoms and greater increases in the development of symptoms of anxiety and depression than were higher TE adolescents, particularly at ages 16 and 17. Interactions did not differ by gender. Findings demonstrate that stress may affect adolescents' likelihood of experiencing anxious/depressed symptoms when they have a low serotonin TE (A/G-modified 5-HTTLPR) genotype and suggest that the vulnerability may be stronger in late than early adolescence.
Project description:BACKGROUND:Adolescence is characterized by substantial changes in sleep behavior, heightened exposure to stressful life events (SLEs), and elevated risk for internalizing problems like anxiety and depression. Although SLEs are consistently associated with the onset of internalizing psychopathology, the mechanisms underlying this relationship remain poorly understood, especially at the within-person level. Here, we leverage a high-frequency longitudinal design to examine sleep as a potential mechanism linking SLEs to increases in anxiety and depression symptoms over a one-year period. METHODS:Thirty female adolescents aged 15-17 years completed 12 monthly in-laboratory assessments of exposure to SLEs and symptoms of anxiety and depression (n = 355 monthly assessments), and wore an actigraphy wristband for continuous monitoring of sleep for the duration of the study (n = 6,824 sleep days). Multilevel models examined concurrent and lagged within-person associations between SLEs, sleep duration and timing regularity, and anxiety and depression symptoms. RESULTS:Within-person fluctuations in SLEs were associated with variability in sleep duration both concurrently and prospectively, such that when adolescents experienced greater SLEs than was typical for them, they exhibited more variable sleep duration that same month as well as the following month. In turn, within-person increases in sleep duration variability predicted greater anxiety symptoms in the same month and mediated the association between SLEs and anxiety. CONCLUSIONS:These findings highlight sleep disruptions as a mechanism underlying the longitudinal associations between SLEs and anxiety symptoms, and suggest that interventions promoting sleep schedule consistency may help mitigate risk for stress-related psychopathology in adolescence.
Project description:Environmental stress and its interaction with genetic variation are key contributors in the development of depression and anxiety, yet there is a failure to identify replicable genetic variants and gene-interaction effects in the background of these psychiatric symptoms. Recently it has been reported that 5-HTTLPR and NOSI interact with financial but not other types of recent stressors in the development of depression. In the present study we investigated the interaction of GABRA6 rs3219151 and CNR1 rs7766029 in interaction with different types of recent life events on the presence of depression and anxiety in a large general population sample. 2191 participants completed the List of Threatening Experiences questionnaire which covers four categories of stressful life events (financial problems, illness/personal problems, intimate relationships, and social network) experienced over the previous year and the Brief Symptom Inventory for depression and anxiety symptoms. Participants were genotyped for rs3219151 and rs7766029. Data were analyzed with linear regression models with age and gender as covariates. Results indicated that CNR1 rs7766029 interacted significantly with financial but not other types of life events both in case of depression and anxiety symptoms. In contrast, GABRA6 rs3219151 showed a significant interaction with social network related life events in case of anxiety and with illness/personal problem-related life events in case of depression. Our results suggest that the psychological impact of different types of recent stress may be differentially modulated by distinct molecular genetic pathways. Furthermore, in case of certain genetic variants, the occurring psychiatric symptom may depend on the type of stress experienced.
Project description:5-HTTLPR, episodic stressors, depressive and anxious symptoms were assessed prospectively (child and parent report) every 3 months over 1 year (5 waves of data) among community youth ages 9 to 15 (n = 220). Lagged hierarchical linear modeling analyses showed 5-HTTLPR interacted with idiographic stressors (increases relative to the child's own average level over time), but not nomothetic stressors (higher stress exposure relative to the sample), to predict prospective elevations in depressive, but not anxious, symptoms. Youth with copies of the S or L(G) alleles of 5-HTTLPR, who experienced more stressors relative to their typical level, exhibited prospective increases in depressive symptoms over time. These findings suggest that 5-HTTLPR confers susceptibility to depression via stress reactivity.
Project description:BACKGROUND:The serotonin (5-HT) transporter-linked polymorphic region (5-HTTLPR) moderates the relationship between stressful life events and depression. Given the high prevalence of depression in chronic pain, the primary aim of this preliminary study was to investigate the associations between the 5-HTTLPR and the severity of depressive symptoms in a cohort of adults with chronic pain. METHODS:Adults with chronic pain who were consecutively admitted to an outpatient pain rehabilitation program and met inclusion criteria were recruited for study participation (n=277). Individuals were genotyped for the 5-HTTLPR (including rs25531) and categorized as high, intermediate, or low expressors of the 5-HT transporter. The severity of depressive symptoms at admission was measured by using the Center for Epidemiologic Depression scale (CES-D). RESULTS:The distribution of the high-, intermediate-, and low-expressing genotypes was 61 (22%), 149 (54%), and 67 (24%), respectively. The Hardy-Weinberg P-value was 0.204, which indicated no departure from equilibrium. A main effect of 5-HTTLPR was observed for depressive symptoms (P=0.040) where Center for Epidemiologic Depression scale (CES-D) scores were significantly greater in the low-expressing group compared to the high- (P=0.019) and intermediate (P=0.029)-expressing groups. In multivariate multinomial logistic regression analysis adjusted for age, sex, pain severity, pain catastrophizing, and pain anxiety, greater CES-D scores were significantly associated with the 5-HTTLPR low-expressing group compared to the high-expressing group (P=0.023), but not for the low-expressing group compared to the intermediate-expressing group (P=0.056). CONCLUSION:These preliminary findings suggest that the triallelic 5-HTTLPR could influence the severity of depressive symptoms in adults with chronic pain. Individuals with chronic pain may be particularly vulnerable to the moderating effects of 5-HTTLPR due to high levels of pain-related stress that are inherently present in this population.
Project description:An adverse psychological environment (e.g. stressful events or depression) has been shown to influence basal cortisol levels and cortisol response to stress. This differs depending on the adverse stimuli, but also varies across individuals and may be influenced by genetic predisposition. An insertion/deletion polymorphism in the serotonin transporter gene (5-HTTLPR) is a strong candidate in this regard.To investigate how stressful life events and depression are associated with diurnal cortisol levels in community-dwelling elderly and determine whether this varies according to genetic variability in the 5-HTTLPR.This population-based study included 334 subjects aged 65 and older (mean (SD) = 76.5 (6.3)). Diurnal cortisol was measured on two separate days, under quiet (basal) and stressful conditions. The number of recent major stressful events experienced during the past year was assessed from a 12-item validated questionnaire as an index of cumulative recent stressful events. Lifetime trauma was evaluated using the validated Watson's PTSD inventory, which evaluates the most severe traumatic or frightening experience according to DSM criteria. Depression was defined as having a Mini-International Neuropsychiatric Interview (MINI) diagnosis of current major depressive disorder or high levels of depressive symptoms (Center for Epidemiologic Studies-Depression Scale ?16). 5-HTTLPR genotyping was performed on blood samples.Exposure to stressful life events was associated with lower basal evening cortisol levels overall, and in the participants with the 5-HTTLPR L allele but not the SS genotype. The greatest effects (over 50% decrease, p < 0.001) were observed for the LL participants having experienced multiple recent stressful events or severe lifetime traumas. Participants with the L allele also had higher evening cortisol stress response. Conversely, depression tended to be associated with a 42% higher basal morning cortisol in the SS participants specifically, but did not modify the association between stressful events and cortisol levels.An adverse psychological environment is associated with basal cortisol levels and cortisol stress response, but this differs according to 5-HTTLPR genotype.
Project description:Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (?30) individuals.Our study is cross-sectional and applies self-report questionnaires.Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
Project description:Posttraumatic stress disorder (PTSD), depression, anxiety, and stress are significant problems among returning veterans and are associated with reduced quality of life.A correlational design was used to examine the impact of a polymorphism (5-HTTLPR) in the serotonin transporter promoter gene on post-deployment adjustment among returning veterans.A total of 186 returning Iraq and Afghanistan veterans were genotyped for the 5-HTTLPR polymorphism. Symptoms of PTSD, depression, general stress, and anxiety were assessed along with quality of life.After controlling for combat exposure, age, sex of the participant, and race, 5-HTTLPR had a significant multivariate effect on post-deployment adjustment, such that S' carriers reported more post-deployment adjustment problems and worse quality of life than veterans homozygous for the L' allele. This effect was larger when the analyses were restricted to veterans of European ancestry.Our findings suggest that veterans who carry the S' allele of the 5-HTTLPR polymorphism may be at increased risk for adjustment problems and reduced quality of life following deployments to war zones.
Project description:BACKGROUND:Previous research reported that individual differences in the stress response were moderated by an interaction between individuals' life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response. RESULTS:Compared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66) = 3.71, P < .001) and also showed increased global methylation as a function of ELS (r (32) = .45, P = .008) and chronic stress (r (32) = .44, P = .010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41) = -.31, P = .042) and increased F3 methylation (r (67) = .30, P = .015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r = .41, P < .01), which correlated positively with NR3C1 expression (r (42) = .31, P = .040). CONCLUSIONS:Both early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals' stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.