The Interaction of Stressful Life Events and a Serotonin Transporter Polymorphism in the Prediction of Episodes of Major Depression

Virginia Institute for Psychiatry and Behavioral Genetics, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23298, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 06/2005; 62(5):529-35. DOI: 10.1001/archpsyc.62.5.529
Source: PubMed


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?
To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings.
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.
A population-based sample of adult twins.
Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1).
Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month.
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.
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.

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    • "The long " L " and the short " s " functional variants (Heils et al., 1995) of the 5-HTTLPR have received great attention because the " s " allele has been associated with decreased transcription efficiency of the 5-HTT gene(Lesch and Mossner, 1998), thereby decreasing the density of 5-HTT in presynaptic neurons and increasing the intensity and duration of the serotonin signaling (Glatz et al., 2003). However, because several large studies have failed to associate the 5-HTTLPR polymorphism with depression (Caspi et al., 2003), this polymorphism may only moderate the influence of stressful life events and when exposed to stressful life events, individuals with the " s " allele could be at a greater risk for developing depression than those with the " L " allele (Caspi et al., 2003;Eley et al., 2004;Kendler et al., 2005;Wilhelm et al., 2006;Zalsman et al., 2006). Imaging genetic studies associated the 5-HTTLPR polymorphism with altered function and morphology of brain regions and circuits that modulate mood and cognition. "
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    ABSTRACT: Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The “s” allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.
    Full-text · Article · Jan 2016 · Psychiatry Research: Neuroimaging
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    • "Lastly, the majority of the prior studies used measures of depressive symptomatology at a single time-point as the outcome while few included more than one assessment of depression per individual to account for within-person fluctuations over time (Araya et al. 2009; Caspi et al. 2003; Chorbov et al. 2007; Jacobs et al. 2006; Kendler et al. 2005; Kilpatrick et al. 2007; Kim et al. 2007; Middeldorp et al. 2007; Ming et al. 2013; Wilhelm et al. 2006). Issues highlighted in the meta-analyses and reviews revolve around heterogeneity in methodology applied to the design of each attempted replication. "
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    ABSTRACT: Depending on genetic sensitivity to it, stress may affect depressive symptomatology differentially. Applying the stress-diathesis hypothesis to older adults, we postulate: (1) recent stress will associate with increased depressive symptoms levels and (2) this effect will be greater for individuals with at least one short allele of the serotonin transporter gene promoter region (5-HTTLPR). Further, we employ a design that addresses specific limitations of many prior studies that have examined the 5-HTTLPR x SLE relation, by: (a) using a within-person repeated-measures design to address fluctuations that occur within individuals over time, increase power for detecting GxE, and address GE correlation; (b) studying reports of exogenous stressful events (those unlikely to be caused by depression) to help rule out reverse causation and negativity bias, and in order to assess stressors that are more etiologically relevant to depressive symptomatology in older adults. The sample is drawn from the Health and Retirement Study, a U.S. population-based study of older adults (N=28,248; mean age = 67.5; 57.3% female; 80.7% Non-Hispanic White, 14.9% Hispanic/Latino, 4.5% African American; genetic subsample = 12,332), from whom measures of depressive symptoms and exogenous stressors were collected biannually (1994-2010). Variation in the 5-HTTLPR was characterized via haplotype, using two single nucleotide polymorphisms (SNPs). Ordered logit models were constructed to predict levels of depressive symptoms from 5-HTTLPR and stressors, comparing results of the most commonly applied statistical approaches (i.e., comparing allelic and genotypic models, and continuous and categorical predictors) used in the literature. All models were stratified by race/ethnicity. Overall, results show a main effect of recent stress for all ethnic groups, and mixed results for the variation in 5-HTTLPRxStress interaction, contingent upon statistical model used. Findings suggest there may be a differential effect of stressors and 5-HTTLPR on depressive symptoms by ethnicity, but further research is needed particularly when using a haplotype to characterize variation in 5-HTTLPR in population-based sample with a diverse ethnic composition.
    Full-text · Article · Aug 2015 · Behavior Genetics
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    • "This polymorphism produces two predominant variants, short (S) and long (L) alleles, whose presence has been associated with differential predisposition to psychiatric disorders. Individuals carrying one or two copies of the S allele exhibit elevated neuroticism and anxiety (Katsuragi et al., 1999; Lesch et al., 1996; Osher et al., 2000) and depressive symptoms (Caspi et al., 2003; Kendler et al., 2005) when compared to individuals who are homozygous for the L allele. The influence of these alleles is less clear during the postpartum period, though. "
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    ABSTRACT: The postpartum period involves some truly transformational changes in females' socioemotional behaviors. For most women and female laboratory rodents, this includes an improvement in their affective state, which has positive consequences for their ability to sensitively care for their offspring. There is heterogeneity among females in the likelihood of this positive affective change, though, and some women experience elevated anxiety or depression (or in rodents anxiety- or depression-related behaviors) after giving birth. We aim to contribute to the understanding of this heterogeneity in maternal affectivity by reviewing selected components of the scientific literatures on humans and laboratory rodents examining how mothers' physical contact with her infants, genetics, history of anxiety and depression and early-life and recent-life experiences contribute to individual differences in postpartum affective states. These studies together indicate that multiple biological and environmental factors beyond female maternal state shape affective responses during the postpartum period, and probably do so in an interactive manner. Furthermore, the similar capacity of some of these factors to modulate anxiety and depression in human and rodent mothers suggests cross-species conservation of mechanisms regulating postpartum affectivity. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Hormones and Behavior
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