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Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response.

ABSTRACT: There has been significant controversy whether stressful life events (SLEs) experienced over the lifespan may elevate the risk of depression in individuals who are homozygous for the short (S) allele of the repeat length polymorphism (5-HTTLPR) in the regulatory region of the serotonin transporter gene (SLC6A4), compared with individuals homozygous for the long (L) allele. On the basis of the hypothesis that age may be a critical variable, by which such a gene-by-environment interaction may be present in younger adults, but not in older adults and in children, aim of this study was to investigate the role of 5-HTTLPR and SLEs on the endocrine stress response in multiple age cohorts. A total of 115 children (8-12 years), 106 younger adults (18-31 years), and 99 older adults (54-68 years) were subjected to the Trier Social Stress Test (TSST) and structured interviews on SLEs. The TSST induced significant endocrine stress responses in all groups. There was a main effect of genotype in younger and older adults with individuals homozygous for the more active L allele showing a significantly larger cortisol response to the TSST than individuals carrying at least one of the low-expressing S alleles. As predicted, there was a significant interaction of 5-HTTLPR genotype and SLEs, but this interaction was only significant in younger adults and only when the measured SLEs had occurred during the first 5 years of life, suggesting that both age and the specific type of SLE has a role in whether a significant gene-environment interaction is observed.

SUBMITTER: Mueller A

PROVIDER: S-EPMC3096802 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response.

Mueller Anett A Armbruster Diana D Moser Dirk A DA Canli Turhan T Lesch Klaus-Peter KP Brocke Burkhard B Kirschbaum Clemens C

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110302 7

There has been significant controversy whether stressful life events (SLEs) experienced over the lifespan may elevate the risk of depression in individuals who are homozygous for the short (S) allele of the repeat length polymorphism (5-HTTLPR) in the regulatory region of the serotonin transporter gene (SLC6A4), compared with individuals homozygous for the long (L) allele. On the basis of the hypothesis that age may be a critical variable, by which such a gene-by-environment interaction may be p ...[more]

PMID: 21368747

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Project description:Scientific enthusiasm about gene × environment interactions, spurred by the 5-HTTLPR (serotonin transporter-linked polymorphic region) × SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings highlight the need for further research. Converging evidence suggests that the effects of 5-HTTLPR genotype may be neurodevelopmental in origin, but we are not aware of empirical studies that have investigated whether the 5-HTTLPR genotype × SLE interaction predicts preschool-onset depression (PO-MDD), the earliest validated form of depression.Children (n = 234) aged 3-5 were recruited for a longitudinal study designed to examine PO-MDD. In a comprehensive baseline assessment, the child's primary caregivers completed questionnaires and were interviewed about their child's behaviors, psychiatric symptoms, and exposure to SLEs.A 5-HTTLPR × SLEs interaction emerged, such that children homozygous for the short allele were more susceptible to depression in the context of elevated SLE than long allele carriers. In contrast, at low SLE exposure, short allele homozygotes had fewer depressive symptoms. The data were best fit by a plasticity model with a substantial reduction in fit by diathesis-stress models.Extending studies in adult and adolescent populations, these data suggest that 5-HTTLPR genotype may provide plasticity to environmental influence, for better or worse. Specifically, children homozygous for the short allele were more susceptible to the depressogenic effects of SLEs but benefitted, in the form of reduced depressive symptoms, in the context of relatively benign environmental conditions (i.e. relatively low SLE exposure). These data highlight the importance of examining gene × environment interactions across development, environment, and outcome but should be interpreted cautiously given the small sample size.

Project description:ContextSubstantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression.ObjectiveTo conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data.Data sourcesSearch of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis.Study selectionCriteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data.Data extractionLogistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression.ResultsIn the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data.ConclusionThis meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

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Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response.

Publications

Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response.

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