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.