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Sensitizing effect of early adversity on depressive reactions to later proximal stress: Moderation by polymorphisms in serotonin transporter and corticotropin releasing hormone receptor genes in a 20-year longitudinal study

Published online by Cambridge University Press:  25 November 2014

Lisa R. Starr*
University of Rochester
Constance Hammen
University of California, Los Angeles
Christopher C. Conway
University of California, Los Angeles
Elizabeth Raposa
University of California, Los Angeles
Patricia A. Brennan
Emory University
Address correspondence and reprint requests to: Lisa R. Starr, Department of Clinical and Social Sciences in Psychology, University of Rochester, 491 Meliora, Box 270266, Rochester, NY 14627; E-mail:


Previous research supports gene–environment interactions for polymorphisms in the corticotropin hormone receptor 1 gene (CRHR1) and the serotonin transporter gene linked polymorphic region (5-HTTLPR) in predicting depression, but it has rarely considered genetic influences on stress sensitization processes, whereby early adversities (EA) increase depressive reactivity to proximal stressors later in life. The current study tested a gene–environment–environment interaction (G × E × E; specifically, gene–EA–proximal stress interaction) model of depression in a 20-year longitudinal study. Participants were assessed prospectively for EA up to age 5 and recent chronic stress and depressive symptoms at age 20 and genotyped for CRHR1 single nucleotide polymorphism rs110402 and 5-HTTLPR. EA predicted stronger associations between recent chronic stress and depression, and the effect was moderated by genes. CRHR1 A alleles and 5-HTTLPR short alleles were associated with greater stress sensitization (i.e., greater depressive reactivity to chronic stress for those also exposed to high levels of EA). The results are consistent with the notion that EA exposure results in neurobiological and cognitive–emotional consequences (e.g., altered hypothalamic–pituitary–adrenal axis functioning), leading to emotional distress in the face of recent stressors among those with certain genetic characteristics, although further research is needed to explore explanatory mechanisms.

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