Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition

Background: Behavioral inhibition to the unfamiliar (BI), a heritable temperamental profile involving an avoidant response to novel situations, may be an intermediate phenotype in the development of anxiety disorders. Corticotropin-releasing hormone (CRH) is a key mediator of the stress response through its effects on the hypothalamic-pituitary-adrenal axis and limbic brain systems. Transgenic mice overexpressing CRH exhibit BI-like behaviors, implicating this gene in the development of the phenotype. Methods: We genotyped a marker tightly linked to the CRH locus in 85 families of children who underwent laboratory-based behavioral assessments of BI and performed family-based association analyses. Results: We observed an association between an allele of the CRH-linked locus and BI (p = .015). Among offspring of parents with panic disorder, this association was particularly marked (p = .0009). We further demonstrate linkage disequilibrium between this marker and single nucleotide polymorphisms encompassing the CRH gene. Conclusions: These results are consistent with the possibility that variants in the CRH gene are associated with anxiety proneness.