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

Abstract

Context The initial report of an interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression is perhaps the best-known and most cited finding in psychiatric genetics. Two recent meta-analyses explored the studies seeking to replicate this initial report 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 explored the relationship between 5-HTTLPR, stress and depression. Objective We sought to perform a meta-analysis including all relevant studies assessing whether 5-HTTLPR moderates the relationship between stress and depression. Data Sources We identified relevant articles from previous meta-analyses and reviews and a PubMed database search. Study Selection We excluded two studies presenting data that were included in other, larger, studies already included in our meta-analysis to avoid duplicate counting of subjects. Data Extraction In order to perform a more inclusive meta-analysis, we used the Liptak-Stouffer Z-score method to combine findings of primary studies at the significance test level rather than raw data level. Results 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<0.0001). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafo studies p=0.16; Risch studies p=0.11). This suggests that the difference in results between previous meta-analyses and ours was not due to the difference in meta-analytic technique but instead to the expanded set of studies included in this analysis. Conclusions Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that 5-HTTLPR moderates the relationship between stress and depression in the studies published to date.

Peer Victimization in Childhood and Internalizing Problems in Adolescence: A Prospective Longitudinal Study

“…Firstly, altered HPA-axis activity and altered cortisol response has been found to be associated with increased risk for developing depression (Burke et al 2005;Cowen 2010;Harkness et al 2011;Luby et al 2004) and altering cognitive processes (El Hage et al 2009;Erickson et al 2003;Huffziger and Kuehner 2009). Furthermore, an interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression has been repeatedly reported with a recent meta-analysis of 54 studies showing 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) (Karg et al 2011). Indeed, victimized children who later develop clinically significant symptoms show systematic differences in the expression of depression-linked genes (e.g.5-HTTLPR) compared to those who remain symptom-free or exhibit only transient symptoms (Sugden et al 2010).…”

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

“…Further, the effects of early-life stress may interact with heritable variation in serotonergic genes to shape individual differences in anxiety and depression risk. Within humans, variants that affect serotonergic function, such as the serotonin transporter polymorphism, interact with early-life stress to shape disease susceptibility (Caspi et al, 2003;Karg et al, 2011;Kendler et al, 2005). Similarly, phenotypes displayed by animal models of altered serotonergic function, such as 5-HTT and 5-HT1A knockout mice, are sensitive to environmental exposure (Carola and Gross, 2012;Zanettini et al, 2010).…”

Letter to the Editor: Bias in the measurement of bias. Letter regarding ‘Citation bias and selective focus on positive findings in the literature on the serotonin transporter gene (5-HTTLPR), life stress and depression’

“…On the other hand, inclusive meta-analyses from Karg et al (2011) (k = 54) and Sharpley et al (2014) (k = 81) both reach positive conclusions, with Sharpley et al (2014) showing that the meta-analytic effect emerges across four separate design subtypes. Karg et al (2011) show that differences between the negative meta-analyses and theirs are due to paper selection, not meta-analytic technique. Papers selected for their statistically homogeneous designs tend to have methodological flaws including retrospective lifetime stress and depression assessment (Moffitt & Caspi, 2014) leading to confounding (Uher & McGuffin, 2010).…”

“…Papers selected for their statistically homogeneous designs tend to have methodological flaws including retrospective lifetime stress and depression assessment (Moffitt & Caspi, 2014) leading to confounding (Uher & McGuffin, 2010). Moreover, Karg et al (2011) show that reports with more robust measures of stress (interview and Zhang (2009a) 'In addition, the individuals carrying the L/L genotype of 5-HTTLPR could be susceptible to MDD when exposed to negative life events and MDD in the Chinese population' 5-HTTLPR, Serotonin transporter gene; RD, risk difference; CI, confidence interval; BDNF, brain-derived neurotrophic factor; OR, odds ratio; SNP, single nucleotide polymorphism; MDD, major depressive disorder; G × E, gene-environment interaction.…”