The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation

Abstract

Context: 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.

Objective: To perform a meta-analysis including all relevant studies exploring the interaction.

Data sources: We identified studies published through November 2009 in PubMed.

Study selection: We excluded 2 studies presenting data that were included in other larger studies.

Data extraction: 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.

Data synthesis: 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.

Conclusion: 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.

Figure 1. Forest plot for the 54 studies included in the meta-analysis

The boxes indicate the one-tailed p value for each study, with lower values corresponding to greater stress sensitivity of s allele carriers and higher values corresponding to greater stress sensitivity of l allele carriers. The size of the box indicates the relative sample size. The triangle indicates the result of our overall meta-analysis. Labels: Magenta - study included only in the Munafo meta-analysis; Cyan - study included only in the Risch meta-analysis; Blue - study included both in the Munafo and the Risch meta-analysis. * Risch et al included only a subset of this study (Gillespie et al, N=1091).