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

ABSTRACT 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, Sep 28, 2015
1 Follower
118 Reads
  • 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.
    Personality and Individual Differences 12/2015; 87:278-281. DOI:10.1016/j.paid.2015.08.028 · 1.86 Impact Factor
  • Source
    • "with reports showing that 5HTTLPR moderates the relationship between stress and depression (Caspi et al., 2003; Karg et al., 2011). Our study has a few important limitations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent research has suggested that a functional polymorphism in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region, 5HTTLPR) may be implicated in gene-environment interactions leading to major depressive disorder (MDD). Our study examined the association between 5HTTLPR and clinical variables of MDD in the Japanese population. We genotyped 5HTTLPR in 216 patients with MDD and 213 age- and sex-matched controls. The genotype distributions and allele frequencies were similar in the patients and controls. When the relationships between the polymorphism and several clinical variables (i.e., age of onset, number of episodes, presence of psychotic features, suicidal behavior, and family history) were examined, the dose of the long (l) allele had significant effects on the age of onset. These results suggest that 5HTTLPR may not be entirely related to the development of MDD but may be related to the age of onset of MDD, which may be due to gene-environment interactions in the Japanese population. Because of the low frequencies of psychotic features and suicidal behavior, our results must be treated with caution until they are replicated in larger numbers of Japanese samples. MDD patients did not undergo a structured interview. Clinical information from the medical records may have not been complete. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 09/2015; 183. DOI:10.1016/j.jad.2015.05.009 · 3.38 Impact Factor
  • Source
    • "This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. environmental influence (Belsky & Pluess, 2009), particularly when objective measures rather than self-reports are employed (Karg et al., 2011; Serretti, Kato, De Ronchi, & Kinoshita , 2007). Based on this information, and in parallel to other studies examining related downstream emotional and/or psychophysiological correlates of 5-HTTLPR genotype (Beevers et al., 2009; Gotlib, Joormann, Minor, & Hallmayer, 2008; McCaffery, Bleil, Pogue- Geile, Ferrell, & Manuck, 2003), we analyzed our data by comparing S= homozygotes to L carriers. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic variation in the serotonergic system within the brain has been a significant focus of psychiatric research over the last several decades. In particular, the serotonin transporter (5-HTT) gene (SLC6A4) has been tied to early emotion processing biases. However, a clear understanding of how genetic variation of SLC6A4 may influence clinically salient emotional phenomena is still elusive. In this investigation, we focused on examining variation in the 5-HTT-linked polymorphic region (5-HTTLPR; including the single nucleotide polymorphism rs25531 which alters genotype interpretation) and real-time emotion responses evoked in the laboratory using a paradigm designed to spontaneously induce emotion regulation. Across 2 studies we show that for healthy individuals with 2 copies of the functional short (S=) allele there is weakened down-regulation of negative emotion. In addition, we found greater electrodermal responses as well as both negative and positive emotion in association with the S= allele in 1 of the 2 samples. These findings provide evidence that the S= allele may promote system-wide heightened emotional reactivity in healthy subjects. Both phenomena, observed here in a healthy population, are strongly linked to the development of psychiatric disease. As such, these findings have implications for S= carriers' vulnerability to affective disorders, as well as suggest potential targets for future clinical investigation.
    Psychology and Neuroscience 09/2015; 8(3):397-413. DOI:10.1037/pne0000017
Show more