Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis

Abstract

Background: We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship.

Methods: We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry.

Results: Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes.

Conclusions: Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.

Figure 1

Meta-analysis of association studies of 5-HTTLPR genotype and amygdala activation. Meta-analysis indicates significant association between 5-HTTLPR genotype and amygdala activation (p < .001). Bars represent individual study 95% confidence intervals, with a central block proportional to study size. The summary diamond bar represents the pooled effect size estimate and 95% confidence interval (CI).

Figure 2

Association between year of publication and effect size estimate. Year of publication is negatively associated with individual study effect size (p = .028), with this trend reflecting a decrease in individual study effect size over time. Removal of the first published study results in a significant reduction in pooled effect size estimate (p < .001), although the effect of 5-HTTLPR genotype remains significant.