The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder

Background. Behavioral inhibition to The unfamiliar (BI) is a heritable temperamental phenotype involving the tendancy to display fearful, avoidant, or shy behavior in novel situations. BI is a familial and developmental risk factor for panic and phobic anxiety disorders. We previously observed an association between BI and a microsatellite marker linked to the corticotropin releasing hormone (CRH) gene in children at risk for panic disorder. To evaluate this further we genotyped additional families for this marker and a panel of markers encompassing the CRH locus. Methods. Sixty-two families that included parents with panic disorder and children who underwent laboratoy-based behavioral observations were studied. Family-based association tests and haplotype analysis were used to evaluate the association between BI and polymorphisms spanning the CRH locus. Results: We examined a set of markers which we found to reside in a block of strong linkage disequilibrium encompassing the CRH locus. The Biphenotype was associated with the microsatellite marker (p =.0016) and three single nucleotide polymorphisms (SNPs), including a SNP in the coding sequence of the gene (p =.0,43). Haplotype-specific tests revealed association with a haplotype comprising all of the markets (p =.015). Conclusions. These results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders, Genetic studies of anxiey-related temperament represent an important strategy,for identifying the genetic basis of anxiety disorders.