Serotonin transporter genotype 5HTTLPR as a marker of differential susceptibility? A meta-analysis of child and adolescent gene-by-environment studies

Abstract

We present results of a meta-analysis of gene-by-environment (G × E) studies involving the serotonin transporter genotype 5HTTLPR to evaluate empirical support for two competing conceptual frameworks in developmental psychopathology: diathesis-stress and differential susceptibility. From a diathesis-stress perspective, the cumulative negative effects of the short allele (ss and sl genotypes) and adverse environments on development have been stressed. From a differential-susceptibility perspective, carriers of the s allele are predicted to be more open to adverse as well as positive environments, for better and for worse. Studies with children and adolescents up to 18 years of age (N=9361) were included. We found 41 effect sizes (N=5863) for the association between negative environments and developmental outcomes with or without significant moderation by 5HTTLPR genotype and 36 effect sizes (N=3498) for the potentially 5HTTLPR-moderated association between positive environments and developmental outcomes. Five moderators were examined: age, ethnicity, genotyping (biallelic or triallelic) and methods used to assess environment and outcome. In the total set of studies, including studies with mixed ethnicities, we found that ss/sl carriers were significantly more vulnerable to negative environments than ll carriers, thus supporting the diathesis-stress model. In the Caucasian samples, however, ss/sl carriers also profited significantly more from positive environmental input than ll carriers. Associations between (positive or negative) environment and (positive or negative) developmental outcome were absent for ll carriers. The meta-analytic findings support the hypothesis that in Caucasian samples 5HTTLPR is a genetic marker of differential susceptibility. G × E interactions might be critically dependent on ethnicity.