Identification of Susceptibility Genes for the Anxiety Disorders

描述（由申请人提供）：焦虑症在人群中非常普遍，并带来严重的痛苦和损害。目前的治疗是有限的，而且，与其他精神疾病相比，对焦虑症的研究相对被忽视了。探索其遗传决定因素将有助于阐明其原因并指导预防和新治疗的研究。我们建议在一个独特的人类遗传流行病学样本中测试从小鼠和人类初步数据中选择的候选焦虑障碍易感基因。我们使用多变量结构方程模型来确定广泛性焦虑障碍、惊恐障碍、广场恐怖症、社交恐惧症、重度抑郁症和神经质相关表型的共同遗传风险因素，样本来自基于人群的弗吉尼亚成人双胞精神病学和物质使用障碍研究。根据从分析中提取的遗传因素的极值得分，从每对可获得DNA的双胞胎中选出一个成员作为病例或对照。589例病例和539例对照的结果样本将进入两个阶段的关联研究，在第一阶段筛选候选基因座，在第二阶段测试其阳性结果的复制性。选择这种两阶段设计是为了降低基因分型成本和控制错误发现率。将使用来自整个样本的一组高信息量匿名标记基因分型的数据来评估和控制群体分层的潜在偏倚。来自小鼠恐惧相关表型的全基因组关联研究的主要数据将用于确定一组初步的候选基因组区域。这将与来自人类和动物焦虑表型全基因组连锁和关联研究的其他数据相结合，以选择一组较小的高优先级候选基因用于我们的人类样本测试。单倍型标记和功能多态性snp，如果有的话，将使用标准算法从公开可用的数据库中选择，以合并这些候选基因区域的遗传变异的主要来源。据我们所知，这是第一次系统地整合来自恐惧相关表型的主要动物研究与人类焦虑障碍数据的信息，以确定这些疾病的易感基因。

DESCRIPTION (provided by applicant): Anxiety disorders are highly prevalent in the population and carry a significant burden of distress and impairment. Current treatments are limited, and, compared to other psychiatric conditions, research in anxiety disorders has been relatively neglected. Exploring their genetic determinants will help elucidate their causes and guide research for prevention and new treatments. We propose to test candidate anxiety disorder susceptibility genes selected from preliminary mouse and human data in a unique human genetic epidemiologic sample. We used multivariate structural equation modeling to identify common genetic risk factors for related phenotypes of generalized anxiety disorder, panic disorder, agoraphobia, social phobia, major depression, and neuroticism 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 is selected as a case or control based upon scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls will be entered into a two- stage association study in which candidate loci are screened in stage 1, the positive results of which are tested for replication in stage 2. This two-stage design was chosen to reduce genotyping costs and control false-discovery rates. Potential bias from population stratification will be assessed and controlled using data from a set of highly-informative anonymous markers genotyped in the entire sample. Primary data from a whole-genome association study in mouse fear-related phenotypes will be used to identify a preliminary set of candidate genomic regions. This will be integrated with other data from genome-wide linkage and association studies in human and animal anxiety phenotypes to select a smaller set of high-priority candidate genes for testing in our human sample. Haplotype-tagging and functional polymorphic SNPs, where available, will be chosen from publicly-available databases using standard algorithms to incorporate the main sources of genetic variation across these candidate gene regions. To our knowledge, this is the first application to systematically integrate information derived from primary animal studies of fear-related phenotypes with human anxiety disorder data to identify the susceptibility genes for these conditions.