The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited

Department of Human Genetics, University of Wuerzburg, Wuerzburg, Germany.
Archives of general psychiatry (Impact Factor: 14.48). 05/2011; 68(5):444-54. DOI: 10.1001/archgenpsychiatry.2010.189
Source: PubMed


Two recent meta-analyses assessed the set of studies exploring the interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have assessed the relationship between 5-HTTLPR, stress, and depression.
To perform a meta-analysis including all relevant studies exploring the interaction.
We identified studies published through November 2009 in PubMed.
We excluded 2 studies presenting data that were included in other larger studies.
To perform a more inclusive meta-analysis, we used the Liptak-Stouffer z score method to combine findings of primary studies at the level of significance tests rather than the level of raw data.
We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (P = .00002). When stratifying our analysis by the type of stressor studied, we found strong evidence for an association between the s allele and increased stress sensitivity in the childhood maltreatment (P = .00007) and the specific medical condition (P = .0004) groups of studies but only marginal evidence for an association in the stressful life events group (P = .03). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafò et al studies, P = .16; Risch et al studies, P = .11). This suggests that the difference in results between meta-analyses was due to the different set of included studies rather than the meta-analytic technique.
Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that the studies published to date support the hypothesis that 5-HTTLPR moderates the relationship between stress and depression.

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    • "The S-allele (SS/SL) of the 5-HTTLPR polymorphism gears individuals' attention toward negative stimuli and emotions (Fox, Ridgewell, & Ashwin, 2009). Individuals who have the S allele tend to be more financially risk-averse (Kuhnen & Chiao, 2009) and more susceptible to depression and anxiety in response to negative experience than those who lack the S-allele (Caspi et al., 2003; Karg et al., 2011). Following the gene–environment interaction view, I argue that although democracy (an environmental factor) fosters social trust (a sociopsychological factor) at the societal level, this positive relationship is moderated by the society's 5-HTTLPR S-allele prevalence (a population-genetic factor), which is strongly correlated with population neuroticism (Minkov, Blagoev, & Bond, 2015). "
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    ABSTRACT: Adopting a gene-environment interaction view, the current research investigated the 5-HTTLPR S-allele prevalence as a moderator for the linkage between democracy and social trust at the societal level. The empirical analysis of 58 societies reveals that the interaction of democracy and the 5-HTTLPR S-allele prevalence is negatively related to social trust, even when a climatoeconomic (climatic demands × wealth) model of social trust is accounted for. The positive relationship between democracy and social trust only exists in societies with the lower 5-HTTLPR S-allele prevalence and is absent in societies with the higher 5-HTTLPR S-allele prevalence. The current findings not only provide important implications for research on social trust across cultures but also add to the emerging literature on gene-environment interactions.
    Personality and Individual Differences 12/2015; 87:278-281. DOI:10.1016/j.paid.2015.08.028 · 1.95 Impact Factor
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    • "This has led to a series of studies examining the extent to which variation in the serotonin transporter gene (5-HTT) might increase risk for depression. While the findings are somewhat mixed, past research has provided evidence that possessing the short allele of 5-HTT increases the probability that stressful events will lead to depression (Karg et al., 2011). In particular, guided by the differential susceptibility perspective (Belsky and Pluess, 2009), recent studies revealed that the short allele of 5-HTT enhances a person's sensitivity to environmental influence, whether that influence be adverse (i.e., " for worse effects " ) or supportive (i.e., " for better effects " ). "
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    ABSTRACT: Introduction: Social scientists have long recognized the important role that neighborhood crime can play in stress-related disease, but very little is known about potential biosocial mechanisms that may link the experience of living in high-crime neighborhoods with depression. Objective: The current study introduces an integrated model that combines neighborhood, genetic, and epigenetic factors. Methods: Hypotheses were tested with a sample of 99 African American women from the Family and Community Health Study (FACHS). Results: Allele variants of the serotonin transporter gene (5-HTT) interact with neighborhood crime to predict depressive symptoms in a manner consonant with the differential susceptibility perspective. Furthermore, this association is mediated by DNA methylation of the promoter region of the serotonin transporter gene. Conclusion: The findings provide support for an integrated model in which changes in DNA methylation, resulting from neighborhood crime, can result in an increase or decrease in gene activity which, in turn, influences depressive symptoms.
    Social Science & Medicine 12/2015; 146:120-128. DOI:10.1016/j.socscimed.2015.10.035 · 2.89 Impact Factor
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    • "Despite this being the most widely investigated GxE in psychiatry, numerous studies including meta-analyses have produced discrepant results (Risch et al. 2009; Karg et al. 2011; Uher, 2014). There is more consistent evidence for an interaction between 5-HTTLPR and CT, conferring risk for persistent depression in adulthood (Karg et al. 2011; Uher et al. 2011; Brown et al. 2013; Fisher et al. 2013). Nevertheless, the conflicting results from GxE studies in psychiatry have made these findings controversial (Duncan & Keller, 2011). "
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    ABSTRACT: Background: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. Method: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. Results: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10-6). SLEs and CT were also associated with MDD status (p = 2.19 × 10-4 and p = 5.12 × 10-20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. Conclusions: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.
    Psychological Medicine 11/2015; DOI:10.1017/S0033291715002172 · 5.94 Impact Factor
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