Gene-environment interactions between stress and 5-HTTLPR in depression: A meta-analytic update

Background: Meta-analyses have yielded contradictory findings concerning the role of 5-HTTLPR in interaction with stress (GxE) in depression. The current meta-analysis investigates if these contradictory findings are a result of differences between studies in methodological approaches towards the assessment of stress and depression. Methods: After performing a systematic database search (February to December 2016), first, a meta-analysis was used to investigate the total effect size and publication bias. Second, stratified meta-analyses were used to investigate the potential moderating influence of different methodological approaches on heterogeneity of study findings. Third, a meta-regression was used to investigate the combined influence of the methodological approaches on the overall effect size. Results: Results showed a small but significant effect of 5-HTTLPR in interaction with stress in the prediction of depression (OR[95% CI] = 1.18[1.09; 1.28], n = 48 effect sizes from 51 studies, totaling 51,449 participants). There was no evidence of publication bias. Heterogeneity of effect sizes was a result of outliers and not due to different methodological approaches towards the assessment of stress and depression. Yet, there was some evidence that studies adopting a categorical and interview approach to the assessment of stress report higher GxE effects, but further replication of this finding is needed. Limitations: A large amount of heterogeneity (i.e., 46%) was not explained by the methodological factors included in the study and there was a low response rate of invited studies. Conclusions: The current meta-analysis provides new evidence for the robustness of the interaction between stress and 5-HTTLPR in depression.