Purpose of review: Human observational studies have shown that, in interaction with life stress, the short or S-allele of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with an enhanced risk for depression. However, this gene-by-environment interaction (G×E) has recently been questioned by two meta-analyses. We aim to provide an overview and appraisal of recent developments and controversies.
Recent findings: The statistical approach of the meta-analyses aimed at a very strict replication of the initial finding and, accordingly, included only a minority of all available studies. Furthermore, the negative results of the meta-analyses appear to be predominantly driven by a few large studies that used retrospective, self-report measures of life stress. In contrast, among 19 studies using interview-based or more objective measures of stress, there were 13 replications, five part-replications and only one nonreplication. Finally, a broader approach based on evidence from different research fields and methodologies supports a 5-HTTLPR by stress interaction.
Summary: Whereas there is no doubt that the meta-analyses are methodologically sound, it appears that this technique is only in part suitable for appraising all of the available evidence. Furthermore, convergent evidence is accumulating from different research fields that 5-HTTLPR is indeed closely associated with different biological pathways associated with stress regulation and depression.