Genetics of Anxiety Disorders

描述（由申请人提供）： 摘要焦虑症是美国人群发病的主要原因，在某些情况下，甚至是死亡的主要原因，特别是在退伍军人中。该项目的目标是确定影响焦虑症易感性的基因，特别是恐慌症（PD）和社交恐惧症（SocP），以及焦虑特征。在以前的工作中，我们收集了一组焦虑症扩展家系，通过先证者与PD确定，并完成了基因组范围内的连锁扫描的几个焦虑性状。最近，我们专注于关联范式，并确定RGS 2作为一个基因，可以影响焦虑表型，CNTNAP 2作为一个基因，可以影响选择性缄默症的风险。我们还专注于创伤后应激障碍（PTSD），有几篇关于GxE相互作用和PTSD的经常被引用的出版物。在过去的资助期间，我们能够利用NIH资助的物质依赖研究招募的大量受试者样本，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。我们建议继续对已经收集的临床资料进行调查，并继续收集Murray Stein博士（UCSD和San Diego VA）确定的一组大学年龄受试者（目前，>1800名受试者）。这些都是项目和合作的证明生产力。我们之前的努力为我们提供了一个很好的临床资源来识别焦虑症风险基因（1084例PD患者和795例SocP患者，不包括圣地亚哥样本中诊断为这些疾病的受试者）。在弗吉尼亚州康涅狄格州，我们将收集120个新的SSADDA确定的DSM-IV PD和SocP受试者每年，共480个受试者-招募率与我们以前取得的一致。这些受试者，加上上文已经确定和列举的PD和SocP受试者，将为我们提供充分把握度的病例对照样本。在加州大学圣地亚哥分校，我们的合作者将收集以下4年中的每一年：150名测量焦虑相关特质的学生，20名惊恐障碍患者和40名SocP患者（即600名特质焦虑受试者，80名PD受试者和160名SocP受试者）。这将使我们总共有>2400名特质焦虑受试者。我们已经获得了初步的SocP GWAS数据的基础上，样本量为250受影响（和一个更大的一组未受影响）。我们建议将社交恐惧症GWAS增加300名受试者。这仍然是一个中等规模的样本，但是，应该提供有趣的新线索，并提供基础，允许我们的完整的SocP样本（第1年和第2年）的基因分型。在第3年和第4年，我们将完成150名受影响受试者的外显子组测序（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个选自单一家系，8个选自另外8个家系。我们对这些数据的初步分析将为我们处理150个额外受试者的大型数据集以及下一个基因测序的数据处理和分析问题做好准备。最后，将在整个焦虑样本（分类诊断和特质焦虑）中对可能相关的常见变异（通过GWAS鉴定）和罕见变异（通过外显子组测序鉴定）进行基因分型。该项目迄今为止已经取得了很高的成效，在其应用的连锁和关联范例，以确定染色体区域可能窝藏基因影响焦虑症的风险和焦虑相关的性状。继续 这项工作将建立在已经收集的宝贵样本和积累的焦虑症遗传分析知识和专门知识的基础上。

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.