Associations between hypothalamic-pituitary-adrenal axis system gene variants and cortisol reactivity in preschoolers: Main effects and gene-environment interactions

Abstract

Exposure to stressful events during early development has consistently been shown to produce long lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to mood and anxiety disorders. Recently reported genetic association studies indicate that these disorders may be influenced, in part, by gene-environment interactions (GxE) involving polymorphisms within the corticotrophin-releasing hormone and monoaminergic system genes. However, little is known about how genetic variants and life stress work to shape children’s neuroendocrine reactivity and emerging symptoms. Therefore, the aim of this thesis is to examine main effects of candidate genes and GxE on the neuroendocrine stress response and internalizing symptoms in a community sample of 409 preschoolers. In Chapter 2 analyses show associations between variants of the CRHR1 and CRHBP genes and children’s cortisol responses to a standardized laboratory stress task. I also found evidence for GxE, where variants of the CRH system genes moderated the impact of childhood stress on early-emerging symptoms of depression and anxiety. A functional polymorphism of the catechol-O-methyltransferase (COMT) gene, the val158met, has been implicated in the etiology of stress-related mood disorders. Therefore, in Chapter 3, I examined links between the val158met polymorphism, cortisol reactivity to stress, and internalizing symptoms. I found evidence for association between the val158met genotype and cortisol reactivity to stress. Additionally, the val158met genotype moderated the link between childhood stress and emerging symptoms of anxiety. Due to the proposed role of dopamine and serotonin gene polymorphisms in research on GxE in internalizing disorders, in Chapters 4 and 5, I examined whether associations between dopaminergic and serotonin candidate gene polymorphisms and childhood cortisol reactivity and internalizing symptoms were moderated by childhood life stress. Analyses showed evidence for GxE predicting children’s symptoms. Specifically, polymorphisms of DRD2 and DAT1 genes moderated the effect of childhood stress on emerging symptoms of anxiety. With regard to serotonin pathway polymorphisms, I found associations between the serotonin transporter promoter polymorphism (5-HTTLPR) and children’s anxious symptoms. Additionally, consistent with previously reported findings, the interaction between MAOA 30bp VNTR and childhood stress predicted child anxiety symptoms. Limitations of this work include a relatively small sample size for genetic analyses, as well as the examination of a limited number of markers at each gene. Additionally, I did not correct for multiple statistical tests in some analyses due to the hypothesis-driven nature of the work. Taken together, the analyses show the complex underpinnings of individual differences in stress regulation, and highlight specific genetic vulnerabilities that influence early psychophysiological reactivity, that may in turn contribute to the development of stress-related disorders later in development