Genetics of Anxiety Disorders
焦虑症的遗传学
基本信息
- 批准号:8542156
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAfrican AmericanAgeAllelesAmericanAnxietyAnxiety DisordersApplications GrantsCandidate Disease GeneCase-Control StudiesChromosome MappingClinicalCollaborationsCollectionComorbidityConnecticutDSM-IVDataData AnalysesData SetDatabasesDiagnosisDiagnosticDiseaseEnrollmentEuropeanExhibitsFunctional disorderFundingFutureGenesGeneticGenotypeGoalsInvestigationKnowledgeLeftLettersLiteratureLocationMeasuresMedicalMethodologyMorbidity - disease rateNatureNormal RangePanic DisorderPatientsPharmaceutical PreparationsPhenotypePopulationPost-Traumatic Stress DisordersPredispositionPrenatal DiagnosisProductivityProphylactic treatmentPublicationsPublishingRGS2 geneRecruitment ActivityResourcesRiskSample SizeSamplingScanningSocial PhobiaStudentsSubstance AddictionSystemTestingTo specifyUnited States National Institutes of HealthVariantVeteransVoluntary MutismWorkaffectionbasecase controlclinical materialcollected workscollegedisorder riskexome sequencingfollow-upfunctional disabilitygenetic analysisgenetic pedigreegenome wide association studygenome-wide linkageimprovedinterestmortalityprobandpublic health relevancesample collectiontraituniversity student
项目摘要
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):
摘要 焦虑症是美国民众尤其是退伍军人群体发病甚至死亡的主要原因。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)以及焦虑特质。在之前的工作中,我们收集了一组通过 PD 先证者确定的焦虑症扩展谱系,并完成了几种焦虑特征的全基因组连锁扫描。最近我们关注关联范式,并确定 RGS2 是一个可以影响焦虑表型的基因,而 CNTNAP2 是一个可以影响选择性沉默症风险的基因。我们还关注创伤后应激障碍 (PTSD),并发表了几篇关于 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,我们能够利用美国国立卫生研究院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,包括焦虑症诊断。我们建议继续对已收集的临床材料进行调查,并继续收集 Murray Stein 博士(加州大学圣地亚哥分校和弗吉尼亚州圣地亚哥)确定的一组大学年龄受试者(目前超过 1800 名受试者)。这些项目和合作已展现出生产力。我们之前的努力为我们提供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这些诊断的受试者)。对于这项工作,我们将采用已经通过其他方法招募的对照受试者NIH 资助的项目:目前我们有 1,020 名筛选的欧洲裔美国人和 832 名筛选的非洲裔美国人对照受试者。在康涅狄格州 VA,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 - 招募率与我们之前取得的成绩一致。这些受试者,连同上面已经确定和列举的 PD 和 SocP 受试者,将为我们留下一个充分有力的病例对照样本。在加州大学圣地亚哥分校,我们的合作者将在接下来的 4 年中每年收集:150 名具有一系列焦虑相关特征的学生、20 名恐慌症患者和 40 名 SocP 患者(即 600 名特质焦虑受试者、80 名 PD 受试者和项目过程中的 160 个 SocP 主题)。这将使我们总共有超过 2400 个特质焦虑对象。我们已经根据 250 个受影响的样本(以及更多未受影响的样本)获得了初步的 SocP GWAS 数据。我们建议将社交恐惧症 GWAS 增加 300 名受试者。这仍然是一个中等大小的样本,但是,应该提供有趣的新线索,并为我们的完整 SocP 样本(第 1 年和第 2 年)的基因分型提供基础。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测序(计划将这些受试者与其他地方的至少 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 个样本选自单个谱系,8 个无关样本选自 8 个其他谱系。我们对这些数据的初步分析将为我们处理由 150 个额外受试者产生的大型数据集以及下一代基因测序特有的数据处理和分析问题做好准备。最后,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)将在整个焦虑样本(分类诊断和特质焦虑)中进行基因分型。迄今为止,该项目在应用连锁和关联范式来识别可能含有影响焦虑症和焦虑相关特征风险的基因的染色体区域方面取得了很高的成果。继续
这项工作将建立在焦虑症遗传分析方面已经很有价值的样本收集和知识和专业知识积累的基础上。
项目成果
期刊论文数量(0)
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JOEL GELERNTER其他文献
JOEL GELERNTER的其他文献
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