Hettema John M, An Seon-Sook, Bukszar Jozsef, van den Oord Edwin J C G, Neale Michael C, Kendler Kenneth S, Chen Xiangning
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298-0126, USA.
Biol Psychiatry. 2008 Aug 15;64(4):302-10. doi: 10.1016/j.biopsych.2008.03.014. Epub 2008 Apr 23.
Catechol-O-methyltransferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits.
We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic risk factor shared by neuroticism, several anxiety disorders, and major depression from a large population-based twin sample. With one member from each of these pairs, the resulting sample of 589 cases and 539 control subjects were entered into a two-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2.
The functional val158met polymorphism (rs4680) plus nine other single nucleotide polymorphism markers selected to capture the major allelic variation across the COMT locus were analyzed for differences between cases and control subjects. Although the val (G) allele of rs4680 showed marginally significant association in our combined stage 1 plus stage 2 sample, a high-risk haplotype of this allele with the A allele of rs165599 was significantly over-represented in cases (p = 1.97e-5, odds ratio = 1.95). This haplotype also predicted individual differences in neuroticism and risk for several anxiety disorders and major depression. Consistent with prior studies, our findings are female-specific.
Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes.
儿茶酚-O-甲基转移酶（COMT）在广泛的精神疾病表型中可能发挥的作用已得到研究。特别是，多项研究支持该基因与惊恐障碍及其他焦虑相关特征之间存在关联。
我们研究了COMT基因与一系列焦虑谱系表型的遗传风险之间的关联。我们使用多变量结构方程模型，从一个基于人群的大型双胞胎样本中，选择在神经质、几种焦虑症和重度抑郁症所共有的潜在遗传风险因素极端得分的双胞胎对。从这些对中的每一对中选取一名成员，将最终得到的589例病例和539名对照受试者样本纳入一项两阶段关联研究，其中在第1阶段筛选遗传标记，其阳性结果在第2阶段进行重复检验。
分析了功能性val158met多态性（rs4680）以及为捕获COMT基因座上的主要等位基因变异而选择的其他9个单核苷酸多态性标记在病例和对照受试者之间的差异。尽管rs4680的val（G）等位基因在我们合并的第1阶段加第2阶段样本中显示出边缘显著关联，但该等位基因与rs165599的A等位基因组成的高风险单倍型在病例中显著过度出现（p = 1.97e-5，优势比 = 1.95）。该单倍型还预测了神经质方面的个体差异以及几种焦虑症和重度抑郁症的风险。与先前的研究一致，我们的发现具有女性特异性。
COMT基因的变异促成了一系列焦虑相关表型所共有的遗传风险。
