A new strategy for the genetic analysis of anxious temperament

Anxious temperament in the form of "behavioral inhibition to the unfamiliar" (BI) is characterized by fearfulness, behavioral inhibition, and autonomic arousal in response to unfamiliar people or situations. Family and twin studies have shown that BI is associated with familial risk of panic and phobic disorders and is under substantial genetic influence. Recent studies have mapped QTL in mice influencing "emotionality" and fear conditioning phenotypes that share the core features of behavioral inhibition and autonomic arousal. Given the extensive synteny homology between mouse and human genomes, these regions may habor loci influencing human anxiety. Method: We are using TDT analysis to study trios in which probands are children with BI drawn from a family study and a longitudinal study of this phenotype. BI was assessed using standardized, behavioral criteria which have demonstrated reliability. Candidate loci are derived from gene mapping and gene manipulation studies of homologous mouse phenotypes. Results: At this time, results are only available for the first 24 trios using candidate loci from mouse chromosome 1. No significant evidence of association has been found yet, but power calculations demonstrate that our anticipated sample size of >100 trios should permit detection of loci of modest effect. Conclusions: Efforts to map genes influencing anxiety disorders have been complicated by the ambiguity of clinical phenotypes and the lack of compelling candidate loci. We hope to overcome these obstacles by exploiting (1) the phenotypic homology between mouse and human anxious temperament and (2) the synteny homology between mouse and human genomes.