Identification of Susceptibility Genes for the Anxiety Disorders

焦虑症易感基因的鉴定

• 批准号: 7179044
• 负责人: JOHN M HETTEMA
• 金额: $ 19.78万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-11 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179044
• 关键词: Adult; Agoraphobia; Algorithms; Animal Model; Animals; Anxiety; Anxiety Disorders; Behavior; Biological; Candidate Disease Gene; Comorbidity; Complex; Condition; Cost Control; DNA; Data; Databases; Detection; Disease; Distress; Equation; Fright; Functional disorder; Gene Targeting; Generalized Anxiety Disorder; Genes; Genetic; Genetic Determinism; Genetic Risk; Genetic Variation; Genomics; Genotype; Haplotypes; Human; Human Genetics; Human Genome; Impairment; Knowledge; Major Depressive Disorder; Medical; Mental disorders; Methodology; Methods; Modeling; Mood Disorders; Mus; Neurotic Disorders; Panic Disorder; Personality; Phenotype; Population; Prevention Research; Probability; Range; Rate; Research; Sampling; Scanning; Score; Screening procedure; Signal Transduction; Social Phobia; Source; Staging; Standards of Weights and Measures; Statistical Methods; Stratification; Substance Use Disorder; Susceptibility Gene; Testing; Twin Multiple Birth; Twin Studies; Variant; Virginia; base; case control; cost; design; genetic association; genetic risk factor; genome wide association study; genome-wide linkage; human data; human study; member; neglect; novel

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.

描述(由申请人提供)：焦虑症在人群中非常普遍，并带有明显的痛苦和损害负担。目前的治疗方法有限，与其他精神疾病相比，焦虑症的研究相对被忽视。探索它们的遗传决定因素将有助于阐明它们的原因，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症易感基因。我们使用多元结构方程模型来识别广泛性焦虑症、恐慌症、广场恐怖症、社交恐惧症、重度抑郁症和神经质的相关表型的常见遗传危险因素，样本来自以人口为基础的弗吉尼亚成人精神和物质使用障碍双胞胎研究。根据从分析中提取的遗传因素的极端评分，从每对可获得DNA的双胞胎中选择一名成员作为病例或对照。589个病例和539个对照的样本将进入两个阶段的关联研究，在阶段1筛选候选基因座，在阶段2检验阳性结果的重复性。选择这个两阶段设计是为了降低基因分型成本和控制错误发现率。将使用在整个样本中进行基因分型的一组信息丰富的匿名标记的数据来评估和控制人口分层带来的潜在偏见。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被用来识别初步的候选基因组区域。这将与来自人类和动物焦虑表型的全基因组联系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在我们的人类样本中进行测试。单倍型标记和功能多态SNP，如果有，将使用标准算法从公开可用的数据库中选择，以纳入这些候选基因区域的主要遗传变异来源。据我们所知，这是第一次系统地将来自恐惧相关表型的初步动物研究的信息与人类焦虑障碍数据相结合，以确定这些疾病的易感基因。