Abstract
We re-evaluate the findings of one of the most cited and disputed papers in gene-environment interaction (GxE) literature. In 2003, a paper was published in Science in which the authors demonstrated that the relationship between stress and depression is moderated by a polymorphism in the promoter region (5-HTTLPR) of the gene SLC6A4. Replication has been weak and led many to challenge the overall significance of GxE research. Here, we utilize data from Add Health, a large, nationally representative, and well-powered longitudinal study to re-examine the genetic determinants of stress sensitivity. We characterize environmental sensitivity using a genome-wide polygenic indicator rather than relying on one polymorphism in a single candidate gene. Our results provide support for the stress-diathesis perspective and validate the scientific contributions of the original paper.