Corticotropin-releasing hormone system polymorphisms are associated with children's cortisol reactivity

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis underlies both adaptive and maladaptive responses to stress and may be an important marker of childhood vulnerability to psychopathology, although little is known about genetic variants that influence cortisol reactivity. We therefore examined associations between corticotrophin-releasing hormone (CRH) system gene (CRH, CRHR1 and CRHBP) variants and cortisol reactivity in preschoolers. A community sample of 409 three-year-old children completed a standardized stress task to elicit HPA axis activation. Salivary samples were obtained at the baseline and at 10-min intervals post-stress for a total of six samples. Salivary cortisol was measured using standard ELISA (enzyme-linked immunosorbent assay) protocols and cortisol reactivity was operationalized by calculating cortisol change scores ([baseline]-[peak cortisol post-stressor]). A single nucleotide polymorphism (SNP) marker panel containing 18 SNPs was used to tag the full-length CRH (4 SNPs), CRHR1 (7 SNPs) and CRHBP (7 SNPs) genes. Significant main effects on children's cortisol reactivity (all ps<0.05) were found for loci on CRHR1 and CRHBP. Haplotypes of the CRHR1 linkage region were also associated with cortisol reactivity (all ps<0.01). Additionally, we found multiple interactions between tag-SNPs in all three gene-coding regions predicting cortisol reactivity (all ps<0.05). Individual differences in children's cortisol reactivity are related to genetic variation in CRH system gene-coding regions. Our results have important implications for future research on the role of HPA axis function in the development of disorders such as anxiety and depression.