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

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 Methods: We used meta-analytic techniques to combine data from existing published and unpublished studies.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did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias.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.