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-VaI/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 similar to339kb 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. Biol Psychiatry 2002;51:591-601 (C) 2002 Society of Biological Psychiatry.