Evidence for a Susceptibility Locus for Panic Disorder near the Catechol-O-Methyltransferase Gene on Chromosome 22 Steven P. Hamilton, Susan L. Slager, Gary A. Heiman, Zemin Deng, Fatemeh Haghighi, Donald F. Klein, Susan E. Hodge, Myrna M. Weissman, Abby J. Fyer, and James A. Knowles Background: A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding se- quence 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 associ- ated 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 © 2002 Society of Bi- ological Psychiatry Key Words: Panic disorder, linkage, association, COMT, family-based, SNPs Introduction S ince the initial description of panic disorder (MIM 167870) as a discrete clinical entity nearly four de- cades ago (Klein 1964), much remains unknown about the etiology of this condition. This relatively common syn- drome (lifetime prevalence of 1%–3% across cultures) is characterized by recurrent panic attacks with concomitant anticipatory anxiety (Weissman et al 1997). Family studies suggest that first-degree relatives of panic probands have a 2.6- to 20-fold relative risk for developing the disorder (Knowles and Weissman 1995). The largest twin study to date reported that heritable factors contribute about 30% to 40% of the diathesis toward panic disorder (Kendler et al 1993). These genetic factors have been the focus of recent work employing genomic (Knowles et al 1998) and candidate gene strategies (Crowe et al 1997; Deckert et al 1999; Hamilton et al 1999, 2000, 2001; Kennedy et al 1999). Investigation into the biological basis of the disor- der has been centered on physiologic parameters, such as carbon dioxide challenge; infusion of sodium lactate, m-chlorophenylpiperazine, or cholecystokinin; and trypto- phan depletion, as well as differential response to medi- cations. Medications that are thought to interact with monoamine and serotonergic systems, such as tricyclic antidepressants, monoamine oxidase A inhibitors, and selective serotonin reuptake inhibitors, have proven effi- cacious in treating panic disorder. This suggests a potential role in panic disorder for proteins involved in the synthe- sis, transport, or catabolism of these neurotransmitters. One such protein in the catabolic pathway is catechol- O-methyltransferase (COMT), an enzyme that catalyzes the extraneuronal methylation of catechol compounds using S-adenosyl-L-methionine as a methyl donor (Boul- ton and Eisenhofer 1998). Analysis of COMT activity in From the Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute (SPH, ZD, DFK, SEH, MMW, AJF, JAK, GAH); Columbia Genome Center, College of Physicians and Surgeons at Columbia University (JAK); Divisions of Biosta- tistics (SEH) and Epidemiology (MMW), Mailman School of Public Health, Columbia University, New York, New York, and Department of Health Sciences Research, Mayo Clinic (SLS), Rochester, Minnesota. Address reprint requests to James A. Knowles, New York State Psychiatric Institute, Unit #28, 1051 Riverside Drive, New York NY 10032. Received May 29, 2001; revised October 1, 2001; accepted October 9, 2001. © 2002 Society of Biological Psychiatry 0006-3223/02/$22.00 PII S0006-3223(01)01322-1