Serotonin transporter gene variants and prediction of stress-induced risk for psychological distress
ABSTRACT The response to psychosocial stress is influenced by both psychosocial factors and genetic vulnerability. The most investigated gene in gene × environment studies in abnormal response to environmental stressors is the one coding for the serotonin transporter (SLC6A4). Variability within this gene has been associated with functional brain differences, personality dimensions, reactivity to stress and risk for various psychopathological conditions. In the present study, we set out to investigate the association of common genetic variants within SLC6A4 with state psychopathology in a community sample homogeneously exposed to stress, thus inquiring about potential genetic differences in stress sensitivity. One thousand eight hundred seventy-five young conscripts were evaluated for psychopathological distress with the 90-item Symptoms Checklist Revised in their first 2 weeks of admission to obligatory military service. Of these, 1594 were genotyped for the biallelic ins/del polymorphism (5-HTTLPR S/L) within the promoter region of SLC6A4, as well as the variation within the 'long' 5-HTTLPR allele (rs25531A/G). Homozygous for the 5-HTTLPR S allele reported significantly higher scores for paranoid ideation as compared with L-allele carriers. Slight effects on other subscales were observed, but were not significant after correction for multiple testing. Despite limitations linked to the evaluation of psychopathology by a single general scale and multiple comparisons, the present study support a role of SLC6A4 in modulating abnormal responses to environmental stress. In particular, variation within this gene may confer risk for paranoid/defensive reactions under conditions of environmental stress associated with military induction.
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ABSTRACT: The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans.PLoS ONE 03/2013; 8(3):e58880. DOI:10.1371/journal.pone.0058880 · 3.53 Impact Factor
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ABSTRACT: In the three years since the most recent meta-analysis of the association between the serotonin transported promoter polymorphism (5-HTTLPR), stress and the development of depression, another 27 studies have been published on this issue, which is an increase of 50% more studies than were previously reviewed. In addition, previous findings of inconsistency of results across studies argued for further exploration of this relationship. From the 81 studies identified to June 2013, the significant relationship between the short form of the 5-HTTLPR was confirmed (p=.0000009), which is stronger than the relationship reported in the most recent meta-analysis in 2011. However, nearly 26% of the 81 studies reviewed failed to show any significant association between the 5-HTTLPR, stress and depression, and four studies found opposite results to those expected. Examination of the methodologies of all studies failed to indicate any flaws in the opposite or unequivocal studies, and the latter had larger sample sizes than those studies which supported the expected association, arguing that the null results were not an outcome of insufficient statistical power. The need to consider aspects of samples and measures of depression, particularly the presence of subtypes of depression in future research is discussed.Behavioural Brain Research 07/2014; DOI:10.1016/j.bbr.2014.07.030 · 3.39 Impact Factor