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Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: a replication and developmental extension.

ABSTRACT: 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.

SUBMITTER: Bogdan R

PROVIDER: S-EPMC3976464 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: a replication and developmental extension.

Bogdan Ryan R Agrawal Arpana A Gaffrey Michael S MS Tillman Rebecca R Luby Joan L JL

Journal of child psychology and psychiatry, and allied disciplines 20131004 5

<h4>Background</h4>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 ...[more]

PMID: 24117502

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Project description:ContextThe 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) has been found to moderate several categories of emotional response after stressful life events. Previous studies generally focused on its effect on depressive symptoms; little is known about its moderation of the development of posttraumatic stress disorder (PTSD).ObjectiveTo examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR genotypes, and gene x environment interactions on the etiology of PTSD.DesignA cross-sectional study in which participants in several studies investigating the genetics of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-HTTLPR was genotyped. Logistic regression modeling was used in the analyses.SettingGeneral community.ParticipantsFive hundred eighty-two European American and 670 African American individuals who reported experiences of childhood adversity, adult traumatic events, or both. Main Outcome Measure Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview.ResultsChildhood adversity and adult traumatic events both predicted PTSD. Although the 5-HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events and childhood adversity to increase the risk for PTSD, especially for those with high rates of both types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI], 1.50-5.45; P = .002; African American: OR, 1.88; 95% CI, 1.04-3.40; P = .04; pooled: OR, 2.31; 95% CI, 1.50-3.56; P < .001).ConclusionsParticipants who had both childhood adversity and adult traumatic events were more likely to develop lifetime PTSD compared with those who experienced either type of adverse event. The risk was increased in individuals with 1 or 2 copies of the S' (S) allele compared with the L' (L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the interactive effect of environmental and genetic factors.

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.

Dataset Information

Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: a replication and developmental extension.

Publications

Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: a replication and developmental extension.

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