Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families.

Background: The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin, and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We have previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., PD definition. Here, we extend this work by carrying out exploratory linkage analyses in this same pedigree set using ten additional literature-based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities.

Methods: Multiply affected families (>2 individuals with PD) were recruited from clinical and nonclinical sources, evaluated by a clinician-administered semistructured interview and a subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric two-point (homogeneity and heterogeneity), multipoint, and nonparametric methods. Empirically based permutations were used to estimate model-specific and global (across all phenotypes) P-values.

Results: The highest score was a two-point lod (4.27, global P<0.08) on chromosome 13 (D13S793, 76 cM) for the phenotype 'specific or social phobia' under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes.

Conclusion: Although the interpretation of findings is limited by the sample size and the large number of phenotypes and models analyzed, these data suggest a region on chromosome 13 as a potential site for further exploration in relation to the risk for specific and social phobias.