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.
"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. "
[Show abstract][Hide abstract] 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.
"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. "
"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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