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.

Download full-text


Available from: Srijan Sen
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2015 · Personality and Individual Differences
  • Source
    • "However, a landmark study that did combine environmental adversity with measures of a copy number variation of a 44 bp repeat in the promoter region of the serotonin re-uptake receptor (5HTT, SLC6A4) showed a highly significant interaction between the 'short' form of this receptor (5HTTLPR) and the occurrence of adverse life events as a positive predictor of subsequent MDD (Caspi et al., 2003). Subsequent replications have been inconsistent, though a recent meta-analysis supports the original finding (Karg et al., 2011). Methodological problems, particularly associated with defining and measuring the incidence or timing of adversity or stressful events, may have contributed to variations in the literature (Hammen et al., 2010; Uher and McGuffin, 2008); for example, the influence of 5HTT variants may be particularly potent on childhood adversity as a predisposition for later MDD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Depression (MDD) is prodromal to, and a component of, Alzheimer’s disease (AD): it may also be a trigger for incipient AD. MDD is not a unitary disorder, so there may be particular subtypes of early life MDD that pose independent high risks for later AD, though the identification of these subtypes is problematical. There may either be a common pathological event underlying both MDD and AD, or MDD may sensitize the brain to a second event (‘hit’) that precipitates AD. MDD may also accelerate brain ageing, including altered DNA methylation, increased cortisol but decreasing DHEA and thus the risk for AD. So far, genes predicting AD (e.g. APOEε4) are not risk factors for MDD, and those implicated in MDD (e.g. SLC6A4) are not risks for AD, so a common genetic predisposition looks unlikely. There is as yet no strong indication that an epigenetic event occurs during some forms of MDD that predisposes to later AD, though the evidence is limited.
    Full-text · Article · Dec 2015 · Frontiers in Neuroendocrinology
  • Source
    • "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 " ). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2015 · Social Science & Medicine
Show more