The Interaction of Stressful Life Events and a Serotonin Transporter Polymorphism in the Prediction of Episodes of Major Depression

CONTEXT: Prior evidence from twin studies suggested genetic moderation of the depressogenic effects of stressful life events (SLEs). Can the specific genes involved in this effect be identified? OBJECTIVE: To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings. DESIGN: Characterizing risk for major depression and generalized anxiety syndrome in the last year as a function of 5-HTT genotype, sex, and the occurrence of SLEs and ratings of the SLE-associated level of threat. SETTING: A population-based sample of adult twins. PARTICIPANTS: Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1). MAIN OUTCOME MEASURE: Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month. RESULTS: Individuals with 2 short (S) alleles at the 5-HTT locus were more sensitive to the depressogenic effects of all SLEs than were those with 1 or 2 long (L) alleles. When level of SLE-associated threat was examined, the interaction between genotype and SLE resulted from an increased sensitivity of SS individuals to the depressogenic effects of common low-threat events. These events had little impact on risk for those possessing the SL and LL genotypes. The 5-HTT genotype did not modify the effects of SLEs on risk for generalized anxiety syndrome. CONCLUSION: Variation at the 5-HTT moderates the sensitivity of individuals to the depressogenic effects of SLEs largely by producing, in SS individuals, an increased sensitivity to the impact of mild stressors. Replication of these intriguing results is needed.