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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    • "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.
    Behavior Genetics 08/2015; DOI:10.1007/s10519-015-9740-8 · 3.21 Impact Factor
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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.
    Hormones and Behavior 07/2015; DOI:10.1016/j.yhbeh.2015.07.016 · 4.63 Impact Factor
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    • "Given that prevalence of SS in European-ancestry populations is 17% (Clarke et al., 2010; Lesch et al., 1996), the numbers suggest that the low-risk group is depleted of SS rather than the high-risk group being enriched for it. Having two copies is associated with increased stress sensitivity (Kendler et al., 2005). Absence of SS may protect against psychobiological responses to stressful events, and is consistent with the lower rates of depressive and anxiety disorders in the low-risk group (Weissman et al., 2006; Weissman et al., 2005). "
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    ABSTRACT: The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N=192) as compared to low (N=101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    04/2015; 228(1). DOI:10.1016/j.psychres.2015.04.015
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