The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication

CONTEXT: Prior evidence from twin studies suggested genetic moderation of the depressogenic effects of stressful life events (SLEs). Can the specific genes involved in this effect be identified? OBJECTIVE: To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings. DESIGN: Characterizing risk for major depression and generalized anxiety syndrome in the last year as a function of 5-HTT genotype, sex, and the occurrence of SLEs and ratings of the SLE-associated level of threat. SETTING: A population-based sample of adult twins. PARTICIPANTS: Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1). MAIN OUTCOME MEASURE: Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month. RESULTS: Individuals with 2 short (S) alleles at the 5-HTT locus were more sensitive to the depressogenic effects of all SLEs than were those with 1 or 2 long (L) alleles. When level of SLE-associated threat was examined, the interaction between genotype and SLE resulted from an increased sensitivity of SS individuals to the depressogenic effects of common low-threat events. These events had little impact on risk for those possessing the SL and LL genotypes. The 5-HTT genotype did not modify the effects of SLEs on risk for generalized anxiety syndrome. CONCLUSION: Variation at the 5-HTT moderates the sensitivity of individuals to the depressogenic effects of SLEs largely by producing, in SS individuals, an increased sensitivity to the impact of mild stressors. Replication of these intriguing results is needed.     

Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.

BACKGROUND: It has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism. METHODS: In 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up. RESULTS: Significant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis. CONCLUSIONS: These findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.     

The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression

OBJECTIVE: Three potent risk factors for major depression are female sex, the personality trait of neuroticism, and adversity resulting from exposure to stressful life events. Little is known about how they interrelate in the etiology of depressive illness. METHOD: In over 7,500 individual twins from a population-based sample, the authors used a Cox proportional hazard model to predict onsets of episodes of DSM-III-R major depression in the year before the latest interviews on the basis of previously assessed neuroticism, sex, and adversity during the past year; adversity was operationalized as the long-term contextual threat scored from 15 life event categories. RESULTS: In the best-fit Cox model for prediction of depressive onsets, neuroticism, female sex, and greater adversity all strongly increased risk for major depression. An interaction was seen between neuroticism and adversity such that individuals with high neuroticism were at greater overall risk for major depression and were more sensitive to the depressogenic effects of adversity. An interaction was also seen between adversity and sex, as the excess risk for major depression in women was confined to individuals with low stress exposure. CONCLUSIONS: Psychosocial adversity interacts both with neuroticism and with sex in the etiology of major depression. The impact of neuroticism on illness risk is greater at high than at low levels of adversity, while the effect of sex on probability of onset is the opposite--greater at low than at high levels of stress. Complete etiologic models for major depression should incorporate interactions between risk factor classes.     

5-HTTLPR moderates effects of current life events on neuroticism: Differential susceptibility to environmental influences

Research chronicling links between a polymorphism in the serotonin-transporter gene (5-HTTLPR) and neuroticism has yielded inconsistent results. One possible explanation for this inconsistency is that any gene–phenotype association is obscured by a gene-X-environment (GXE) interaction. We studied a healthy non-clinical sample (N = 118) to determine whether the 5-HTTLPR interacts with current life events in predicting neuroticism. The differential-susceptibility hypothesis led to the prediction of such an interaction, reflecting the fact that individuals with short alleles would be affected more by both negative and positive life events than those homozygous for long alleles. Participants completed questionnaires concerning recent life events and neuroticism. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid. For those homozygous for the short allele, more negative life events proved related to greater neuroticism, whereas more positive life events proved related to less neuroticism. No such association emerged in the case of those homozygous for the long allele. Whereas neuroticism is likely to be an especially stable trait in individuals homozygous for the long allele, this may be less so the case for those carrying short alleles.     

Serotonin transporter and GABAA alpha 6 receptor variants are associated with neuroticism.

BACKGROUND: A tendency to experience negative affect, as measured by the neuroticism component of the Neuroticism, Extraversion, and Openness Personality Inventory (NEO-PI), is a trait marker for major depression. Epidemiologic studies indicate a strong genetic component, but to date few specific genetic variants have been definitively implicated. A serotonin transporter promoter polymorphism (5-HTTLPR) has been extensively studied in neuroticism and several psychiatric disorders, with inconclusive results. A GABA(A) receptor alpha6 subunit variant (Pro385Ser) has been associated with alcohol-related traits but has not been studied in neuroticism or depression. METHODS: A total of 384 subjects who completed the NEO-PI were genotyped at 5-HTTLPR and Pro385Ser. Associations between polymorphisms and both alcohol use and personality domains were tested. RESULTS: The 5-HTTLPR short allele (p =.008) and Pro385Ser Pro allele (p =.003) are associated with higher neuroticism scores. The 5-HTTLPR long allele (p =.006), but not Pro385Ser, is also associated with an increased presence of alcohol use. In addition, there is a nonsignificant suggestion of an interaction: the effect of 5-HTTLPR on neuroticism might be dependent on the Pro385Ser genotype. CONCLUSIONS: These findings support a role for the serotonin transporter and GABA(A) alpha6 subunit in depression-related traits.     

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.     

Variations in 5-HTTLPR: Relation to familiar risk of affective disorder,life events,neuroticism and cortisol

Background

Variations in the serotonin transporter gene (5-HTTLPR) and stressful life events are associated with affective disorders.

Aim

To investigate whether the distribution of the alleles of the 5-HTTLPR is associated with a genetic predisposition to affective disorder and whether these variations interact with life events in relation to depressive symptoms, neuroticism and salivary cortisol.

Method

In a high-risk population study, healthy monozygotic and dizygotic twins with (high-risk twins) and without (low-risk twins) a co-twin history of affective disorder were identified through nationwide registers.

Results

When comparing the 81 individuals homozygote for the long allele with the 125 individuals hetero- and homozygote for the short allele no associations between the allele distribution and a genetic predisposition were found. The presence of the short allele of the 5-HTTLPR and the experience of SLE was associated with a higher neuroticism score, but not with depressive symptoms nor awakening or evening salivary cortisol.

Conclusion

A combination of variants in 5-HTTLPR and environmental stress seems to increase neuroticism in healthy individuals.     

5-羟色胺转运体基因多态性与青少年抑郁症的关联研究

目的 探讨中国汉族青少年抑郁症与5-羟色胺转运体（5-HTY）基因的启动子区多态（5-HTTLPR）之间的关系。方法 应用聚合酶链式反应（PCR）扩增技术对84例青少年抑郁症患者和85例健康者进行基因型分析。结果 5-HTYLPR基因的3种基因型S／S,L／S和L/L在青少年抑郁症组的分布分别为57．1％,36．9％,6．0％;在对照组分别为57．6％,34．1％,8．2％,两组间差异无显著性（P〉0．05）。抑郁症组中S／S基因型患者HAMD自杀因子评分明显高于L／L和L／S型患者（P〈0.01）。结论 5-HTT基因多态性与青少年抑郁症无明显关联。抑郁症中携带S／S基因型患者的自杀风险相对比L／L型、L／S型患者高。     

Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.

BACKGROUND: Mixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample. METHODS: A nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid. RESULTS: A stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype. CONCLUSIONS: Early or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.     

The effect of serotonin transporter gene promoter polymorphism on adolescent and adult ADHD symptoms and educational attainment: A longitudinal study

IntroductionThe purpose of this longitudinal study was to investigate the relationship between the 5-HTTLPR genotype, symptoms of ADHD in adolescence and adulthood, and educational attainment in a population representative sample. Neuroticism, depressive symptoms and general mental abilities were controlled for as possible confounding factors.MethodsADHD symptoms were reported at age 15 and 18 by teachers using the Hyperactivity Scale of af Klinteberg and SNAP-IV, and self-reported at age 25 using the ASRS. Data about education were reported at age 25.ResultsAt age 15, subjects with the l/l genotype had more concentration difficulties compared to s-allele carriers, and they also had more inattention symptoms according to SNAP-IV at age 18. These results were not altered by taking neuroticism or depressive symptoms into account. No 5-HTTLPR genotype effect on self-reported ADHD symptoms at age 25 was found. Inattention symptoms in adolescence were associated with lower education in young adulthood. The proportion of subjects with higher education at age 25 was significantly larger among s/s genotype compared to the l/l or s/l genotype.ConclusionsThe l/l genotype of the 5-HTTLPR is associated with inattentive symptoms during adolescence in the general population, and increases the likelihood of inferior educational level in young adulthood.     

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.     

Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression

OBJECTIVE: The lower expressing allele of the serotonin transporter gene 5' promoter region (5-HTTLPR) polymorphism is reported to be associated with susceptibility to depression and suicidality in response to stressful life events. The authors examined the relationship of a triallelic 5-HTTLPR polymorphism to stressful life events, severity of major depression, and suicidality. METHOD: Mood disorder subjects (N=191) and healthy volunteers (N=125), all Caucasian subjects of European origin, were genotyped for the triallelic 5-HTTLPR polymorphism (higher expressing allele: L(A); lower expressing alleles: L(G), S). All subjects underwent structured clinical interviews to determine DSM-IV diagnoses, ratings of psychopathology, stressful life events, developmental history, and suicidal behavior. CSF 5-HIAA was assayed in a subgroup of subjects. RESULTS: Lower expressing alleles independently predicted greater depression severity and predicted greater severity of major depression with moderate to severe life events compared with the higher expressing L(A) allele. No associations with suicidal behavior and CSF 5-HIAA were found. CONCLUSIONS: Lower expressing transporter alleles, directly and by increasing the impact of stressful life events on severity, explain 31% of the variance in major depression severity. The biological phenotype responsible for these effects remains to be elucidated.     

Cognitive appraisal and life stress moderate the effects of the 5-HTTLPR polymorphism on amygdala reactivity

The short allele of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is associated with increased amygdala activation in response to emotional stimuli. Although top-down processes may moderate this association, available evidence is conflicting, showing the genotype influence on amygdala reactivity to be either decreased or increased during emotion regulation. Because the effects of the 5-HTTLPR polymorphism on amygdala reactivity are also conditional on self-reported life stress, differences in life stress exposure may account for this apparent discrepancy. Here, we hypothesized that self-reported life stress would moderate the relationships between genotype, cognitive appraisal, and amygdala reactivity. Forty-five healthy never-depressed subjects were presented with emotional stimuli and performed two cognitive tasks: a self-referential task and an emotion-labeling task. Life-stress exposure was measured through a semistructured interview. First, there was a genotype × condition interaction in the right amygdala: short allele carriers displayed increased amygdala activation and decreased functional connectivity with the subgenual anterior cingulate cortex in self-referential processing versus emotion labeling. Second, in line with our hypothesis, there was a genotype × condition × stress interaction in bilateral amygdala the amygdala activation during self-referential processing was negatively correlated with self-reported life stress in short allele carriers and positively in individuals homozygous for the long allele, whereas an opposite pattern was observed during emotion labeling. These results confirm that the influence of the 5-HTTLPR polymorphism on amygdala reactivity is at least partially under cognitive control. Additionally, they suggest that measuring life stress exposure is a critical step when imaging genetics.     

Perceptions of the family,personality characteristics,and adolescent internalizing symptoms

OBJECTIVE: To explore the influences of adolescent self-reported and interviewer-rated perceptions of family functioning, parent perceptions of the family, and adolescent personality on internalizing symptoms. METHOD: Two hundred one adolescent twins (mean age = 16.2 +/- 2.0 years; 90% white) completed the Family Assessment Device (FAD), Eysenck Personality Inventory, Children's Depression Inventory, and Multidimensional Anxiety Scale for Children and participated in an interview about their relationships with parents. Parents completed the FAD. Twins were divided into two samples for analysis. RESULTS: Multiple regression analyses in sample A showed that adolescent perceptions of family function accounted for 35% of the variance in depressive symptoms, but did not significantly predict anxiety. Self-reported perceptions were more strongly associated with symptoms than were interviewer-rated perceptions. Parent FAD and adolescent neuroticism accounted for 24% of the variance in adolescent self-reported perceptions. Results were similar in sample B. CONCLUSIONS: Adolescent perceptions of the family are linked to their depressive symptoms and associated with neuroticism. Adolescents who are high in neuroticism may perceive their families more negatively. Clinicians need to carefully discern components of family function that lead to teen depression versus biased cognitions that lead teenagers to perceive family relationships as negative.     

The interplay and etiological continuity of neuroticism, difficulties, and life events in the etiology of major and subsyndromal, first and recurrent depressive episodes in later life

OBJECTIVE: Stressful life events, long-term difficulties, and high neuroticism are established risk factors for depression. Less is known about their role in late-life depression, how they modify or mediate one another's effects, and whether this differs between major and subsyndromal, first and recurrent episodes. METHOD: The authors used a prospective case-control design nested in a community survey of elderly subjects that included a measure of neuroticism. They compared 83 survey participants who subsequently developed a depressive episode with 83 randomly selected comparison participants. The authors determined dates of onset, history, and severity of episodes and dates of occurrence and severity of stressful life events and difficulties. RESULTS: Stressful life events did not mediate the effects of high neuroticism and difficulties at onset, possibly because of the uncontrollable nature of common stressful life events in later life. Without both high neuroticism and difficulties, stressful life events did not increase risk. High neuroticism and difficulties increased risk, even without a stressful life event. In the presence of high neuroticism and/or difficulties, the depressogenic effect of stressful life events was substantial, suggesting effect modification. The authors found no evidence to suggest etiological discontinuity between major and subsyndromal episodes. First and recurrent episodes showed a discontinuous pattern of associations. Severe stressful life events had weaker associations, but high neuroticism and mild stressful life events had stronger associations with recurrent than with first episodes. CONCLUSIONS: This study demonstrated the usefulness of a dynamic stress-vulnerability model for understanding late-life depression. Evidence was found suggesting etiological discontinuity between first and recurrent but not between major and subsyndromal episodes.     

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.     

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.     

Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior

Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism-a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability-increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs.