Genetics of Anxiety Disorders

描述(由申请人提供)： 摘要焦虑症是美国总体人群中发病率的主要原因，在某些情况下还会导致死亡，特别是在退伍军人中。拟议项目的目标是确定影响焦虑症易感性的基因，特别是惊恐障碍(PD)和社交恐惧症(SOCP)，以及焦虑特征。在以前的工作中，我们收集了一组通过帕金森病先证者确定的焦虑症扩展家系，并完成了对几个焦虑性状的全基因组连锁扫描。最近，我们重点研究了关联范式，发现RGS2是影响焦虑表型的基因，CNTNAP2是影响选择性沉默风险的基因。我们还关注创伤后应激障碍(PTSD)，有几本经常被引用的关于GxE相互作用和PTSD的出版物。在过去的资助期间，我们能够利用为NIH资助的物质依赖研究招募的大样本受试者，在这些研究中，我们获得了全面的诊断信息，包括焦虑症的诊断。我们建议继续我们对已经收集的临床材料的研究，并继续收集由Murray Stein博士(加州大学圣迭戈分校和弗吉尼亚州圣地亚哥分校)确定的一组大学年龄受试者(目前，&gt；1800名受试者)。这些都是证明了工作效率的项目和协作。我们之前的努力为我们留下了识别焦虑症风险基因的良好临床资源(1084名PD患者和795名SOCP患者，不包括圣地亚哥样本中具有这些诊断的受试者)。为了这项工作，我们将使用已经通过NIH资助的其他项目招募的对照受试者：目前，我们有1020名筛选的欧洲裔美国人和832名筛选的非裔美国人对照受试者。在康涅狄格州退伍军人管理局，我们每年将收集120名新的SSADDA-确定的DSM-IV PD和SOCP受试者，总共480名受试者--这一招聘率与我们之前取得的成就一致。这些受试者，加上上文已经确定和列举的PD和SOCP受试者，将为我们留下一个足够有力的病例对照样本。在加州大学圣迭戈分校，我们的合作者将收集以下4年中的每一年的数据：150名测量了一系列焦虑相关特征的学生，20名惊恐障碍患者，40名SOCP患者(即项目过程中600名特质焦虑症受试者，80名PD受试者，160名SOCP受试者)。这将给我们留下总共2400个特质焦虑受试者。我们已经根据250个受影响的样本大小(以及更大的一组未受影响的样本)获得了初步的SOCP Gwas数据。我们建议将社交恐惧症扩大300个额外的科目。然而，这仍然是一个中等大小的样本，应该会提供有趣的新线索，并为我们的完整SOCP样本(第一年和第二年)进行基因分型提供基础。在第三年和第四年，我们将完成150名受影响的受试者的外周基因组测序(计划将这些受试者与其他地方提供的至少300名对照受试者进行比较)。我们已经完成了20个PD样本的外显子组测序，其中12个样本选自一个家系，8个无关样本选自另外8个家系。我们对这些数据的初步分析将为我们处理来自150个额外主题的大型数据集以及特定于下一个基因测序的数据处理和分析问题做好准备。最后，在整个焦虑症样本(分类诊断和特质焦虑症)中，将对可能相关的常见变异(通过GWAS鉴定)和罕见变异(通过外显子序列鉴定)进行基因分型。到目前为止，该项目在应用连锁和关联范例来识别可能含有影响焦虑症风险和焦虑相关特征的基因的染色体区域方面取得了很高的成效。延续 这项工作将建立在已经很有价值的样本收集和焦虑症基因分析知识和专业知识的积累的基础上。

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.