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Evidence of Synergism in Shaping Risk of Depression

Nele Jacobs, PhD; Gunter Kenis, PhD; Frenk Peeters, MD, PhD; Catherine Derom, PhD; Robert Vlietinck, MD, PhD; Jim van Os, MD, PhD

Arch Gen Psychiatry. 2006;63:989-996.

Context  Genetic moderation of the depression-inducing effects of stressful life events (SLEs) has been reported, but findings suggest that genes may not moderate the effects of SLEs per se but instead may moderate the risk of depression associated with the stable tendency to develop negative emotions in response to minor environmental experiences.

Objective  To examine whether a functional polymorphism of the serotonin transporter gene (5-HTTLPR) moderates the association between negative affectivity (neuroticism) and depression and to what degree this can explain previous findings involving SLEs.

Design  A prospective cohort study involving 1 baseline and 4 follow-up measurements in 15 months analyzing change in self-reported depressive symptoms across time as a function of negatively attributed SLEs, neuroticism, 5-HTTLPR, and their interactions.

Setting  General community.

Participants  A population-based sample of 374 ethnically homogeneous young adult female twins.

Main Outcome Measure  A continuous score of self-reported depressive symptoms.

Results  The depressogenic effect of SLEs in the 3 months before interview was significantly greater in women with 2 short (S) alleles compared with women with 1 or none. However, this effect disappeared after accounting for the effect of SLEs conditional on neuroticism. Similarly, the depressogenic effect of neuroticism was progressively greater with number of S alleles, and this was unchanged after accounting for the effect of neuroticism conditional on SLEs.

Conclusions  Genotype x environment interactions in depression may be more productively interpreted by involving mechanisms more proximal to psychological experience itself. The probability that stress-related cognitive vulnerabilities for depression result in symptom formation may be moderated by a neurobiologic phenotype characterized by altered processing of negative emotions associated with variation in 5-HTTLPR.

Author Affiliations: Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON (Drs Jacobs, Kenis, Peeters, and van Os), and Department of Population Genetics (Dr Vlietinck), Maastricht University, Maastricht, the Netherlands; Faculty of Medicine, Center for Human Genetics, Catholic University Leuven, Leuven, Belgium (Drs Derom and Vlietinck); and Division of Psychological Medicine, Institute of Psychiatry, London, England (Dr van Os).

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