Genetics of Anxiety Disorders

焦虑症的遗传学

• 批准号: 8668742
• 负责人: JOEL GELERNTER
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668742
• 关键词: Affect; African American; Age; American; Anxiety; Anxiety Disorders; Applications Grants; Candidate Disease Gene; Case-Control Studies; Chromosome Mapping; Clinical; Collaborations; Collection; Comorbidity; Connecticut; DSM-IV; Data; Data Analyses; Data Set; Databases; Diagnosis; Diagnostic; Disease; Enrollment; European; Exhibits; Functional disorder; Funding; Future; Genes; Genetic; Genotype; Goals; Investigation; Knowledge; Left; Letters; Literature; Location; Measures; Medical; Methodology; Morbidity - disease rate; Nature; Normal Range; Panic Disorder; Patients; Pharmaceutical Preparations; Phenotype; Population; Post-Traumatic Stress Disorders; Predisposition; Prenatal Diagnosis; Productivity; Prophylactic treatment; Publications; Publishing; RGS2 gene; Recruitment Activity; Resources; Risk; Sample Size; Sampling; Scanning; Social Phobia; Students; Substance Addiction; System; Testing; To specify; United States National Institutes of Health; Variant; Veterans; Voluntary Mutism; Work; affection; base; case control; clinical material; collected works; college; disorder risk; exome sequencing; follow-up; functional disability; genetic analysis; genetic pedigree; genome wide association study; genome-wide linkage; improved; interest; mortality; proband; public health relevance; rare variant; risk variant; sample collection; trait; university student

DESCRIPTION (provided by applicant): ABSTRACT Anxiety disorders are major causes of morbidity and in some cases, mortality, in the US population in general, and in the Veteran population, specifically. The goal of the proposed project is to identify genes influencing susceptibility for anxiety disorders, especially panic disorder (PD) and social phobia (SocP), and anxiety traits. In previous work we collected a set of anxiety disorder extended pedigrees ascertained through probands with PD, and completed genome wide linkage scans for several anxiety traits. Recently we focused on association paradigms, and identified RGS2 as a gene that can influence anxiety phenotypes, and CNTNAP2 as a gene that can affect selective mutism risk. We have also focused on posttraumatic stress disorder (PTSD), with several frequently-cited publications on GxE interaction and PTSD. In the past funding period, we were able to take advantage of a large sample of subjects recruited for NIH-funded substance dependence studies, in which we obtained comprehensive diagnostic information, including anxiety disorder diagnoses. We propose to continue our investigations in already-collected clinical material, and by continuing collection of a set of college-age subjects ascertained by Dr. Murray Stein (UCSD & San Diego VA) (presently, >1800 subjects). These are projects and collaborations of demonstrated productivity. Our prior efforts have left us with a good clinical resource for identifying anxiety disorder risk genes (1084 PD patients and 795 SocP patients, excluding subjects with those diagnoses in the San Diego sample).For this work we will employ control subjects already recruited via other NIH-funded projects: presently we have 1,020 screened European-American, and 832 screened African-American, control subjects. At VA Connecticut, we will collect 120 new SSADDA-ascertained DSM-IV PD and SocP subjects yearly, a total of 480 subjects - a recruitment rate consistent with what we have achieved previously. These subjects, together with PD and SocP subjects already ascertained and enumerated above, will leave us with an adequately-powered case-control sample. At UCSD, our collaborator will collect for each of the following 4 years: 150 students with range of anxiety-related traits measured, 20 patients with panic disorder, and 40 patients with SocP (i.e. 600 trait-anxiety subjects, 80 PD subjects, and 160 SocP subjects over the course of the project). This will leave us with a total of >2400 trait anxiety subjects. We have obtained preliminary SocP GWAS data based on a sample size of 250 affected (and a much larger set of unaffected). We propose to expand the social phobia GWAS by 300 additional subjects. This will still be a modest-sized sample, however, should provide interesting new leads, and provide the basis to permit genotyping of our full SocP sample (Years 1 and 2). In Years 3 and 4, we will accomplish exomic sequencing of 150 affected subjects (planning to compare these with at least 300 control subjects available elsewhere). We have completed exome sequencing for 20 PD samples, 12 selected from a single pedigree and 8 unrelated selected from 8 additional pedigrees. Our preliminary analysis of these data will prepare us for dealing with the large data set that will result from 150 additional subjects and data handling and analysis issues specific to next-gene sequencing. Finally, possibly-associated common variants (identified through GWAS) and rare variants (identified through exome sequencing) will be genotyped in the entire anxiety sample (categorical diagnoses and trait anxiety). This project has been highly productive to date, in its application of linkage and association paradigms to identify chromosomal regions likely to harbor genes influencing risk for anxiety disorders and for anxiety-related traits. Continuation of this work would build on the already-valuable sample collection and accumulation of knowledge and expertise on genetic analysis of anxiety disorders.

描述（由申请人提供）： 抽象焦虑症是发病率的主要原因，在某些情况下，在美国，总体上，在退伍军人人口中，特别是死亡率。拟议项目的目的是确定影响焦虑症易感性的基因，尤其是恐慌症（PD）和社会恐惧症（SOCP）以及焦虑特征。在先前的工作中，我们收集了一组焦虑症扩展了通过PD的概率确定的焦虑症，并完成了基因组宽连接扫描的几种焦虑特征。最近，我们专注于关联范式，并将RGS2鉴定为一种可以影响焦虑表型的基因，而CNTNAP2是一种可能影响选择性武术风险的基因。我们还专注于创伤后应激障碍（PTSD），并提供了有关GXE相互作用和PTSD的几本经常引用的出版物。在过去的资金期间，我们能够利用用于NIH资助的物质依赖研究招募的大量受试者，其中我们获得了全面的诊断信息，包括焦虑症诊断。我们建议继续对已经收集的临床材料进行调查，并继续收集默里·斯坦（UCSD＆San Diego VA）确定的一组大学时代学科（目前，> 1800名受试者）。这些是展示生产力的项目和合作。我们先前的努力使我们获得了良好的临床资源来识别焦虑症风险基因（1084名PD患者和795名SOCP患者，不包括圣地亚哥样本中具有诊断的受试者）。对于这项工作，我们将采用已通过NIH资助的其他项目招募的控制对象：目前，我们有1,020名筛选的欧洲裔欧洲裔室和832个筛选的非洲人筛选主题，并受到了832个筛选主题。在弗吉尼亚州康涅狄格州，我们每年将收集120个新的SSADDA分类的DSM-IV PD和SOCP受试者，总共有480名受试者 - 这是与我们先前所取得的成就一致的招聘率。这些受试者以及上面已经确定和列举的PD和SOCP受试者将为我们提供足够动力的病例对照样本。在UCSD，我们的合作者将在接下来的4年中收集：150名与焦虑相关性状的学生，有20例恐慌症患者和40名患有SOCP的患者（即600名特质 - 焦虑学科，80名PD受试者，160名SECP受试者，在项目过程中。这将使我们总共拥有> 2400个特质焦虑对象。我们基于250个影响的样本量（以及一组不受影响的一组）获得了初步的SOCP GWAS数据。我们建议将社会恐惧症GWAS扩大300个主题。但是，这仍然是一个适中的样本，但是应该提供有趣的新线索，并提供允许我们完整的SOCP样本基因分型的基础（1年和第2年）。在第3和4年中，我们将完成150名受试者的外部测序（计划将其与其他地方可用的300个对照受试者进行比较）。我们已经完成了20个PD样品的外显子组测序，从单个血统中选择了12个，从8个附加的血统中选择了8个无关。我们对这些数据的初步分析将使我们为处理大型数据集做好准备，这些数据集将由150位其他主题以及数据处理和分析问题引起，并分析了下一基因测序的问题。最后，可能在整个焦虑样本（分类诊断和性状焦虑症）中基因分型，可能与稀有变体（通过GWAS鉴定）和稀有变体（通过外显子测序鉴定）（通过外显子测序鉴定）。迄今为止，该项目的生产力很高，在其应用联系和关联范式的应用中，以识别可能具有影响焦虑症风险和焦虑相关性状风险的基因的染色体区域。延续 这项工作将建立在已经可以实现的样本收集以及焦虑症遗传分析的知识和专业知识的基础上。