Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22

Family, segregation, and twin studies imply a genetic predisposition towards panic disorder, while clinical and animal studies suggest a role for catechol-O-methyltransferase (COMT) in anxiety. A well-characterized single nucleotide polymorphism in the coding sequence of the COMT gene leads to a 3-4-fold difference in COMT activity. Employing a family-based design, 613 individuals in 70 panic disorder pedigrees, as well as 80 Haplotype Relative Risk "triads" were genotyped at the polymorphic COMT locus and the nearby polymorphic microsatellite D22S944, and the data were analyzed for genetic association and linkage. For COMT, linkage analysis employing several diagnostic/ genetic models produced lod scores of 2.60 assuming genetic heterogeneity using a recessive model with narrow/intermediate diagnostic categories. When D22S944 was analyzed, lod scores of 1.47/1.80 were obtained using the same models, as well as a lod score of 2.93 using a broad diagnostic model. Association tests using the triads were not significant for the less informative bi-allelic COMT, but were highly significant for D22S944 using the Haplotype Relative Risk statistic (p = 0.00007) and Transmission disequilibrium Test (p = 0.00004). Further investigation using 8 SNPs and 1 intronic microsatellite are underway. These findings provide strong evidence for a susceptibility locus for panic disorder within the COMT gene or in a nearby region of chromosome 22.