Neuroticism mediates the association of the serotonin transporter gene with lifetime major depression

Background and Objectives: An association between a polymorphism in the serotonin transporter gene (5HTT-LPR) and the personality trait of neuroticism has been reported. We sought to address the question of whether trait neuroticism mediates the putative association between this polymorphism and lifetime major depression in adults drawn from the general population. Methods: Two hundred and fifty-one participants completed the Eysenck Personality Questionnaire and an adapted version of the depression section of the Structured Clinical Interview for DSM-III-R diagnosis, modified for implementation by a self-report questionnaire. A path method was applied to assess the mediator effect of neuroticism on the association between 5HTT-LPR genotype and life-time major depression. Results: 5HTT-LPR genotype was significantly associated with both neuroticism (p = 0.02) and lifetime major depression (p = 0.04), and neuroticism with lifetime major depression (p < 0.001). Neuroticism accounted for 42.3% of the effect of 5HTT-LPR genotype on lifetime major depression, indicating possible mediation (p < 0.001). Conclusions: These results suggest that neuroticism mediates the association between 5HTT-LPR genotype and lifetime major depression, consistent with models of the aetiology of depression which suggest that anxiety-related personality traits represent a substantial risk factor for affective disorder.