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

Background: A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder. Methods: Subjects from 70 panic disorder pedigrees, and 83 "triads", were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and ∼339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage. Results: Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p = .0001-.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p = .0001), as was the "global" p value for this combination (p = .005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder. Conclusions: Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22.