Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism
Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism
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DOI：
10.1038/sj.mp.4001845
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发表时间：
2006-08-01
影响因子：
11
通讯作者：
Chen, X.
中科院分区：
文献类型：
--
作者：
Hettema, J. M.;An, S. S.;Chen, X.
在患有情绪和焦虑障碍的受试者中，γ-氨基丁酸（GABA）神经递质系统存在异常。谷氨酸脱羧酶 (GAD) 从谷氨酸合成 GABA，因此是这些病症的合理候选易感基因。在这项研究中，我们检查了 GAD1 和 GAD2 基因与一系列内化性疾病遗传风险的关联。我们使用多变量结构方程模型来确定重度抑郁症、广泛性焦虑症、惊恐障碍、广场恐惧症、社交恐惧症和神经质 (N) 的常见遗传风险因素，样本来自基于人群的弗吉尼亚成人双胞胎精神和药物使用障碍研究的 9270 名成年受试者。根据从分析中提取的遗传因素的极端评分，从每对双胞胎中选择一名可获得 DNA 的成员作为病例或对照。由此产生的 589 例病例和 539 例对照样本被纳入两阶段关联研究，其中候选基因座在第一阶段进行筛选，其阳性结果在第二阶段进行复制测试。GAD1 区域测试的 6 个单核苷酸多态性中的几个在两个阶段都表现出显着关联，对所有 1128 名受试者的综合分析表明，它们形成了一种常见的高风险单倍型，在病例中显着过高（P = 0.003），效应大小 OR = 1.23。在第一阶段筛选的 14 个 GAD2 标记中，只有一个符合第二阶段随访的阈值标准。该标记加上其他三个在第一阶段形成显着单倍型组合的标记，没有复制它们与第二阶段表型的关联。根据独立样本的确认，我们的研究表明，GAD1 基因的变异可能导致 N 的个体差异，并影响一系列焦虑症和重度抑郁症的易感性。
Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P = 0.003) with effect size OR = 1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.