The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression

BACKGROUND: Serotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression. METHOD: We typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype. RESULTS: There were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction. CONCLUSIONS: Regardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.     

Adult attachment and gene polymorphisms of the dopamine D4 receptor and serotonin transporter (5-HTT)

Recently, the Dopamine D4 Receptor Gene (DRD4) and the Serotonin Transporter Gene (5-HTT) have been found to be candidate genes for infant attachment disorganization. The present study aimed to explore the relationship of these genes to adult attachment representations. The Adult Attachment Interview was used to assess attachment representations in 167 German adults. DNA from buccal cells was genotyped for the DRD4 VNTR Exon III and 5-HTT LPR polymorphisms with respect to the presence of the 7repeat allele and the short allele, respectively. DRD4 7repeat allele carriers were significantly more likely to be securely attached than those without 7repeat but only for subjects with unloving caregiver recollections. No association between the 5-HTT LPR polymorphism and adult attachment was found. These findings encourage further investigations to explore endophenotypical and mediating psychological processes between the DRD4 Gene and secure attachment patterns.     

Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients

Several studies have attempted to confirm an association between a deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTT) and Alzheimer's disease independent from the apolipoprotein E (APOE) varepsilon4 status. We examined this deletion/insertion polymorphism of the serotonin transporter gene in a sample of 222 consecutively recruited gerontopsychiatric patients which was divided into four different diagnostic groups: Alzheimer's disease (N=84), mild cognitive impairment (N=29), subjective cognitive complaints (N=49), depression/other psychiatric disorders (N=56) and 118 healthy, non-demented controls. The aim of this approach was to test whether the investigated polymorphism has a high enough selectivity and specificity to distinguish between the different gerontopsychiatric disorders or to differentiate genetically AD from other forms of dementia, respectively. We could not detect any significant differences in the allelic distribution of the deletion/insertion polymorphism of the 5-HTT gene between the four patient subgroups and the control group. This finding indicates that the serotonin transporter does not appear to be a major susceptibility factor in the pathophysiology of Alzheimer's disease and other psychogeriatric disorders.     

Serotonin transporter gene (5-HTT) polymorphisms and compulsive buying

We examined a panel of 21 patients diagnosed with compulsive buying for two DNA sequence polymorphisms found in the gene that encodes the serotonin transport (5-HTT). One polymorphism, found in the promoter region of the 5-HTT gene, involves a 44-base pair (bp) deletion, and the other, found in the second intron, is due to variable numbers of a repeat sequence. We also typed a panel of 38 psychiatrically normal controls for both 5-HH markers. When compared to this control panel, no significant differences were seen for either 5-HTT marker among the compulsive buyers.     

Serotonin transporter (5-HTT) gene and bipolar affective disorder

Interactions with antidepressants, as well as other biochemical evidence, implicate the serotonin transporter 5-HTT in the etiology of affective disorders. However, genetic studies have produced conflicting results concerning an association of 5-HTT with bipolar disorder. We examined a variable number tandem repeat in the regulatory region of this gene to investigate the possible contribution of 5-HTT to bipolar disorder susceptibility in a 22-pedigree series. By affected-sib-pair analysis and the transmission/disequilibrium test, we found no significant linkage or association of 5-HTT to bipolar disorder. During the course of this study, we adapted a PCR technique designed to amplify long templates to replicating long GC stretches with complex structure. We also refined the location of 5-HTT by radiation hybrid mapping, placing the locus between D17S1294 and SHGC-11022 on 17q11.2. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:37–40, 1998. © 1998 Wiley-Liss, Inc.     

Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population

Serotonin transmission has long been suspected as being involved in the pathogenesis of schizophrenia. 5-HTT is a promising candidate gene for schizophrenia due to its critical role in regulating serotonin transmission and role in the mechanism of the atypical antipsychotic drugs. A common polymorphism STin2 VNTR in the 5-HTT gene has been extensively investigated in the genetic association studies, but the results are conflicting. Meanwhile, the SNPs of the 5-HTT gene have been much less explored. We therefore conducted a case-control study of the association between STin2 VNTR and three tagging SNPs in 5-HTT and schizophrenia in the Han Chinese population based on a cohort of 329 schizophrenic patients and 288 control subjects. No association was found in the single locus, but haplotype-based analyses revealed significant association between two haplotypes with schizophrenia even after Bonferroni correction (P = 0.00000538 and 0.011).     

Serotonin transporter (5-HTT) gene variants associated with autism?

An association study was performed to elucidate the role of the serotonin transporter (5-HTT) gene as a susceptibility factor for autism as treatment of patients with antidepressant drugs which selectively target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior and aggression, and ameliorate language use. Using the transmission/disequilibrium test (TDT) an analysis was done for a common polymorphism in the upstream regulatory region (5-HTTLPR), a VNTR in intron 2 of the gene and a haplotype of both loci in 52 trios fulfilling stringent criteria for autism and an extended group of 65 trios including patients showing no language delay in their first 3 years of life. A higher frequency and preferential transmission of the long allele of the 5-HTTLPR was observed, but the TDT gave a statistically significant value ( P = 0. 032) only for the extended patient group. This result is in contrast to a recent study by a US group presenting preliminary evidence for preferential transmission of the short allele of 5-HTTLPR in 86 trios. Both studies failed to reveal significant linkage disequilibrium between the VNTR in intron 2 of the gene and autism. In our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied evidence for an association of 5-HTT and autism in the stringent ( P = 0.069) and extended patient group ( P = 0.049). Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder. The implications for genetic variants of the serotonin transporter in the etiology of autism and possible subgroups of patients, therefore, needs clarification in further studies with other and larger patient samples.      

Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE

Dysfunctions in serotonergic pathways may underlie several psychiatric disorders. The reuptake of serotonin (5-HT) from synaptic terminals is mediated by a specific transporter (5-HTT). Genetic variation in the gene coding for the 5-HTT protein might be involved in the predisposition to psychiatric disorders. A systematic screening of the whole coding sequence of the 5-HTT gene in mood disorder (MD) and obsessive-compulsive disorder (OCD) patients, as well as in healthy controls, using PCR and denaturing gradient gel electrophoresis (DGGE) revealed the presence of two mutations. The first was in intron 4, and the second was a C → A transversion leading to an amino-acid exchange (Leu → Met) in position 255 of the deduced protein sequence. No further occurrence of this substitution was found in an extended sample of patients and controls. Therefore, structural modifications of the 5-HTT gene do not seem to play either a major or minor role in the genetic predisposition to MD or OCD. © 1996 Wiley-Liss, Inc.     

The integrated model of serotonin transporter gene variation (5HTTLPR) and the glial cell transporter in stress vulnerability and depression

The serotonin transporter gene (SLC6A4) promoter polymorphism (5HTTLPR) has been associated with individual stress responses such that individuals with childhood abuse history have higher rates of depression in later life if they are homozygous short (s/s) of the gene. It is hypothesized that these findings could be explained by an integrated model of a role of the glial cell transporter and a functional difference of 5HTTLPR in the capacity of absorbing serotonin from the synapse.A hypothetical integrated model of the SLC6A4 function and the role of glial cells are put forward to explain accumulating results of recent investigations exploring the relationship between the gene and the diverse mental activities including depression and stress response.A model based on SLC6A4 variation is proposed to explain individual differences in stress vulnerability/resilience. The role of the glial cell transporter surrounding the synapse is integrated in the model to understand the modulation of the neurotransmission. It is hypothesized that a synapse with less serotonin transporter contributes to unstable processing in neurotransmission as compared to a synapse with more serotonin transporter. As such, based on functional differences of 5HTTLPR in the expression of the serotonin transporter, it is asserted that individuals with the s/s genotype process neurotransmission differently and in a reactive way.This integrated model of 5HTTLPR and glial cells suggests that the efficacy of serotonin reuptake in the synapse may play a crucial role in variability of neurotransmission, which can lead to differences in the stress response and the pathophysiology of depression.     

Stressful life events,personal losses,and perimenopause-related depression

Summary We compared the number and quality of life events reported by depressed perimenopausal women and a non-depressed comparison group. Additionally, we examined the effects of the presence of hot flushes on life event reports. All women were 44–55 years old, had irregular menses and elevated plasma gonadotropin levels. The Psychiatric Epidemiology Research Interview recorded both the frequency of occurrence and the desirability of life events experienced by the women during the six months prior to the interview. Depressed perimenopausal women (n=50) reported significantly more undesirable events [Students t-test (unpaired) with Bonferroni correction, t₉₈=3.9, p=0.001] but not more exit events (e.g., divorce, last child leaving home or death in family) (t₉₈=0.9, p=NS) compared to the non-depressed women (n=50). There were no effects of hot flushes on these diagnostic differences. The empty nest syndrome does not appear to be relevant in the development of perimenopausal depression. Nevertheless, independent of the presence of hot flushes, perimenopausal depressed women are more likely to report both negative life events and diminished self esteem.     

The generation of life events in recurrent and non-recurrent depression

BACKGROUND: The stress generation hypothesis proposed by Hammen (1991) holds that depressed individuals generate stressful conditions for themselves, which lead to recurrence. The original test of this hypothesis compared dependent life events in women with recurrent depression to medical and normal controls. Two further research questions emerged from this work: (a) do individuals with a history of many depressive episodes generate more dependent life events than depressives with fewer episodes?; and (b) what is the aetiological relevance of any stress that may be generated? METHODS: The present research tested differences in dependent and independent events between depressed individuals who had experienced: (a) no previous major depressive episodes; (b) one previous episode; and (c) two or more previous episodes. We predicted that, based on the stress generation hypothesis, recurrent depressives would show more dependent events than people without a depression history, and that these generated stressors would be of aetiological importance for precipitating recurrence (i.e. severe events in the 3 months preceding recurrence). RESULTS: Recurrent depressives experienced significantly more total dependent events than first-onset depressives in the 12 months, but not the 3 months, preceding their episode. CONCLUSIONS: Although the findings supported the general premise of stress generation, the aetiological relevance of the generated stress for recurrence requires further study.     

5-羟色胺转运蛋白基因多态性与脑卒中后抑郁的关联

目的:探讨5-羟色胺转运体连锁启动区(5-hydroxytryptamine transporter linked promoter region,5-HTTLPR)基因多态性与脑卒中后抑郁发病、自杀行为是否相关。方法:应用聚合酶链反应(PCR)扩增技术测定中国汉族脑卒中抑郁(poststroke depression,PSD)患者90例(PSD组)和无抑郁脑卒中患者90例(非PSD组)的5-HTTLPR基因型及等位基因,分别验证各种基因型与脑卒中抑郁症发病及自杀行为的相关性。结果:PSD组SS基因型及S等位基因频率(64.4%,75.6%)明显高于非PSD组(38.9%,58.3%),S等位基因携带者PSD患病率为LL型纯合子的1.29倍(OR=1.29,P<0.001,95%CI:1.11～1.50);对PSD组自杀行为分层比较,有自杀行为组SS基因型及S等位基因频率(76.8%,75.6%)明显高于无自杀行为组(44.1%,58.3%),PSD患者中,S等位基因携带者自杀行为发生概率为LL纯合子的1.3倍(OR=1.3,P<0.01,95%CI:1.08～1.6)。结论:5-HTTLPR基因可能是PSD的易感基因,S等位基因可能与PSD及自杀行为相关。     

No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.

In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.     

Stressful life events as a link between problems in nonverbal communication and recurrence of depression

BACKGROUND: Interpersonal difficulties and stressful life events are important etiological factors in (recurrence of) depression. This study examines whether stressful life events mediate the influence of problems in nonverbal communication on recurrence of depression. METHODS: We registered nonverbal expressions of involvement from videotaped behavior of 101 remitted outpatients and their interviewers. During a 2-year follow-up, we assessed stressful life events and recurrence of depression. RESULTS: The less congruent the levels of nonverbal involvement behavior of participants and interviewers, the higher the incidence of stressful life events, and -via these - the risk of recurrence. LIMITATIONS: Nonverbal behavior was measured in an experimental setting. CONCLUSIONS: The results suggest that lack of nonverbal congruence during social interaction contributes to the occurrence of stressful life events, which in turn may trigger depression.     

Stressful events,appraisal, coping and recurrent headache

One hundred fourteen headache sufferers recorded their headaches, stressful events, appraisal processes, and coping responses over a 28 day period. Stressful events were found to precede headache attacks more often than periods of headache freedom. Primary appraisals (how much the event mattered), levels of affective regulation coping and ratings of emotional upset were all higher for stressful events that were not associated with subsequent headache. Stressful events occurring during headache were followed by increases in the intensity of the attack. In such instances, avoidance coping was associated with higher ratings of headache intensity following the event and direct coping with lower post-event ratings. It was concluded that stressful events may be causally related to headache and that the ways in which headache sufferers respond to these events may also have implications for the onset and intensity of attacks. © 1998 John Wiley & Sons, Inc. J Clin Psychol 54: 247–256, 1998.     

An exploratory genetic analysis: Associations between parent depression symptoms,child temperament,and the serotonin transporter gene polymorphism (5HTTLPR)

Child temperament has been shown to be biologically based and heritable; however, genetic association studies of temperament have been fairly inconclusive, and the role that parental depressive symptoms play is largely unexplored in this context. The relationship between parent depressive symptoms and the child temperament dimensions of fear and activity level (AL ) were examined in 100 sibling pairs 2.5–5.5 years of age and their mothers. Parent reports of child temperament and parent self‐reports of depressive symptoms were obtained from families, as well as DNA samples from each child during their lab visit. Associations between the serotonin transporter gene (SLC6A4 ) polymorphism 5‐HTTLPR /rs25531 and the phenotypic variables were also explored. Parent depressive symptoms were significantly related to higher child AL , but minimally associated with fear outcomes. More powerful regression analyses revealed that parent depressive symptoms, child gender, and child age predicted child AL , but only child gender and age predicted child fear. In our exploratory candidate gene analyses, the low‐expressing genotypes of the 5‐HTTLPR /rs25531 polymorphism predicted child fearfulness, but not child AL . Our phenotypic findings indicate that a child with at least one parent with depressive symptoms is more likely to have higher AL , and results of the initial genetic analyses show that the 5‐HTTLPR /rs25531 polymorphism is associated with child fearfulness. Future research employing larger samples, observational assessments, and related child behavioral maladjustment measures will further clarify these findings.