Hamilton Steven P, Slager Susan L, Heiman Gary A, Deng Zemin, Haghighi Fatemeh, Klein Donald F, Hodge Susan E, Weissman Myrna M, Fyer Abby J, Knowles James A
Department of Psychiatry, College of Physicians and Surgeons at Columbia University, New York, NY, USA.
Biol Psychiatry. 2002 Apr 1;51(7):591-601. doi: 10.1016/s0006-3223(01)01322-1.
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.
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 approximately 339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage.
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.
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.
儿茶酚-O-甲基转移酶（COMT）基因编码序列中一个特征明确的单核苷酸多态性（472G/A-Val/Met-SNP8）导致酶活性出现三到四倍的差异，临床和动物研究表明其在惊恐障碍等焦虑状态中发挥作用。
对来自70个惊恐障碍家系和83个“三联体”的受试者进行了7个单核苷酸多态性（SNP）、COMT基因第一内含子中的多态微卫星以及COMT上游约339kb处（D22S944）的基因分型，并分析了遗传关联和连锁情况。
连锁分析显示，使用多种诊断和遗传模型时，472G/A（SNP 8）、沉默外显子3替代（186C/T-SNP 5）和标记D22S944的LOD得分升高（分别为2.88、2.62和2.93）。SNP的关联测试不显著，但D22S944的关联测试高度显著（p = 0.0001 - 0.0003）。由上述三种多态性形成的一个三联体单倍型与惊恐障碍显著相关（p = 0.0001），该组合的“全局”p值也是如此（p = 0.005）。此外，发现许多D22S944与COMT SNP组合的单倍型与惊恐障碍显著相关。
我们的研究结果为惊恐障碍的易感基因座提供了有力证据，该基因座位于COMT基因内或22号染色体的附近区域。
