Gene–environment interactions: early life stress and risk for depressive and anxiety disorders

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Abstract
Rationale Prior reviews have examined how stress, broadly defined, interacts with genetic diathesis in the pathogenesis of internalizing (i.e., depressive and anxiety) disorders. Recent findings have suggested a unique role for early life stress (ELS) in the development of internalizing disorders, contributing to the rapid proliferation of research in this area. Objective This paper critically reviews studies in humans examining gene–environment interaction (GxE) effects of ELS on the risk for depression and anxiety, primarily from a candidate gene perspective. Major methodological challenges that are unique to such studies are considered. Results The majority of published studies have focused on candidates that regulate the serotonin system, especially the serotonin transporter. More recent work has addressed interactions of ELS with candidates from the hypothalamic-pituitary-adrenal axis and neurotrophin system. Available studies vary greatly with respect to definitions of ELS, examination of gene–gene interactions, consideration of gender effects, and attention to analytic limitations. Conclusions Overall, there is support for GxE effects of ELS on the risk for depressive and anxiety outcomes. Future studies of ELS in this context will require careful attention to methodologic considerations. Such studies would benefit from more systematic assessment of positive environmental factors (e.g., social support) and greater utilization of developmentally sensitive paradigms.

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