Hettema J M, An S S, Neale M C, Bukszar J, van den Oord E J C G, Kendler K S, Chen X
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298-0126, USA.
Mol Psychiatry. 2006 Aug;11(8):752-62. doi: 10.1038/sj.mp.4001845. Epub 2006 May 23.
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.
在患有情绪和焦虑障碍的受试者中，已发现γ-氨基丁酸（GABA）神经递质系统存在异常。谷氨酸脱羧酶（GAD）可将谷氨酸合成为GABA，因此，它们是这些疾病合理的候选易感基因。在本研究中，我们检测了GAD1和GAD2基因与一系列内化性障碍的遗传风险的关联。我们使用多变量结构方程模型，在基于人群的弗吉尼亚成人双胞胎精神疾病和物质使用障碍研究的9270名成年受试者样本中，确定重度抑郁症、广泛性焦虑症、恐慌症、广场恐惧症、社交恐惧症和神经质（N）的共同遗传风险因素。根据从分析中提取的遗传因素得分极端情况，为每对有可用DNA的双胞胎中的一人选择作为病例或对照。将得到的589例病例和539例对照样本纳入两阶段关联研究，其中在第1阶段筛选候选基因座，其阳性结果在第2阶段进行重复检验。在GAD1区域检测的6个单核苷酸多态性中有几个在两个阶段均显示出显著关联，对所有1128名受试者的综合分析表明，它们形成了一个常见的高风险单倍型，在病例中显著过度表达（P=0.003），效应大小OR=1.23。在第1阶段筛选的14个GAD2标记中，只有1个符合第2阶段随访的阈值标准。该标记加上在第1阶段形成显著单倍型组合的其他3个标记，在第2阶段未重复其与表型的关联。有待在独立样本中进行确认，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。
