1/8-Collaborative genomic studies of Tourette Disorder

1/8-抽动秽语症的合作基因组研究

• 批准号: 8182787
• 负责人: Gary A. Heiman
• 金额: $ 19.09万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8182787
• 关键词: Affect; Alleles; Attention deficit hyperactivity disorder; Biocompatible Materials; Caucasians; Caucasoid Race; Cell Line; Child; Clinical; Collaborations; Collection; Communities; Comorbidity; Complementary DNA; Complex; Copy Number Polymorphism; DNA; DNA Sequence; Data; Development; Diagnostic; Disease; European; Family; Family member; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Gilles de la Tourette syndrome; Health Benefit; Heterogeneity; Human; Individual; International; Joints; Koreans; Measures; Mental disorders; Molecular; Motor Tics; Mutation; Obsessive-Compulsive Disorder; Parents; Pilot Projects; Population; Prevalence; Public Health; RNA; Recruitment Activity; Research Project Grants; Resources; Risk; Sample Size; Sampling; Site; Symptoms; Syndrome; Techniques; Time; Translating; Tube; Variant; Vocal Tics; base; cost; data management; exome; experience; follow-up; gene discovery; genetic pedigree; genome wide association study; genome-wide; member; neuropsychiatry; next generation; novel; proband

DESCRIPTION (provided by applicant): SUMMARY/ABSTRACT: Tourette Disorder (TD) is a developmental neuropsychiatric syndrome characterized by the combination of persistent vocal and motor tics. While initially considered rare, the world-wide prevalence is now estimated to be 0.3-1%. Both as a consequence of potentially disabling symptoms as well as very high rates of psychiatric co-morbidity, particularly with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), TD represents a significant public health concern. Despite decades of evidence supporting a significant genetic contribution, progress in identifying risk alleles has been slow. This difficulty is thought to be, in part, a consequence of complex inheritance and substantial genetic and phenotypic heterogeneity. This collaborative study unites an international group of highly expert clinicians specializing in TD with statistical and molecular geneticists and is motivated by three central hypotheses: 1) that a key rate- limiting factor for TD gene discovery has been the paucity of publically available, large-scale biomaterial resources of the kind that are now commonplace for many neuropsychiatric disorders; 2) based on recent data from a host of other genetically complex disorders, a comprehensive genomics study of TD will require large samples sizes and should focus on the potential contribution of rare as well as common alleles and both sequence and structural variants; and 3) an increased understanding of the genetic etiology of TD will translate into novel and more effective approaches to treating this often-debilitating disorder, and consequently will have marked public health benefits. The application elaborates three specific aims: Specific Aim 1: To recruit 5050 individuals with TD (and their family members), and make DNA, cell-lines, cDNA/RNA and phenotypic data publicly available within one year of collection. The sample will include a subset of 3195 European Caucasian (EC) probands; 1250 Korean probands, and 3295 parent-child trios allowing for the study of de novo variation. We will also recruit each year at least 10 TD pedigrees with 4 or more affected members as a resource for family-based gene discovery. Specific Aim 2: To employ state-of-the-art techniques to identify and confirm rare and common variants contributing to TD. We will genotype the sample on Illumina HumanOmni2.5 -Quad BeadChips to support copy number variation (CNV) analysis (Aim 2A) and genome wide association studies (GWAS) (Aim 2B); whole exome sequencing will be employed in select, multiply-affected TD pedigrees (Aim 2C); and we will follow up on the most promising loci identified in the aforementioned studies using a pooled next generation re-sequencing strategy (Aim 2D) at two time points, evaluating a minimum of 50 genes in a total of 3195 EC and 3195 matched controls; Specific Aim 3: To perform preliminary analyses of 300 transcriptomes of TD subjects to investigate the implications of selected structural and sequence variations for cis, trans and genome-wide expression. With no cost to this project, PAXgene tubes will be collected from all subjects and made available to the scientific community to enable future studies by our group and others. PUBLIC HEALTH RELEVANCE: Project Narrative: Tourette Disorder (TD) is a poorly understood, often debilitating neuropsychiatric disorder characterized by a combination of persistent vocal and motor tics, affecting between 3 in 1000 and 1 in 100 people worldwide, predominantly children. Our international team of experts in TD and other mental disorders proposes to recruit 5050 affected individuals, undertake a comprehensive gene discovery effort, and make the collected biomaterials and clinical data rapidly available to the broad scientific community, thereby enabling both current and future TD research. Understanding the causes of TD may facilitate the development of novel and improved treatments.

描述（由申请人提供）： 摘要/摘要：抽动秽语症（TD）是一种发育性神经精神综合征，其特征是持续性发声和运动抽动的结合。虽然最初被认为很罕见，但现在估计全世界的患病率为 0.3-1%。由于潜在的致残症状以及极高的精神共病率，特别是强迫症 (OCD) 和注意力缺陷多动障碍 (ADHD)，TD 代表了一个重大的公共卫生问题。尽管数十年的证据支持显着的遗传贡献，但识别风险等位基因的进展缓慢。这种困难被认为部分是复杂遗传以及大量遗传和表型异质性的结果。这项合作研究由专门研究 TD 的国际高水平临床医生小组与统计和分子遗传学家联合起来，并受到三个中心假设的推动：1) TD 基因发现的一个关键限制因素是缺乏公开可用的、大量的基因。规模化生物材料资源，这种资源现在在许多神经精神疾病中很常见； 2) 根据许多其他遗传复杂疾病的最新数据，对 TD 进行全面的基因组学研究将需要大量样本，并应重点关注罕见和常见等位基因以及序列和结构变异的潜在贡献； 3) 对 TD 遗传病因学的深入了解将转化为治疗这种经常使人衰弱的疾病的新颖且更有效的方法，从而对公共健康产生显着的益处。该申请阐述了三个具体目标： 具体目标 1：招募 5050 名 TD 患者（及其家庭成员），并在收集后一年内公开 DNA、细胞系、cDNA/RNA 和表型数据。样本将包括 3195 名欧洲白种人 (EC) 先证者的子集； 1250 名韩国先证者和 3295 名亲子三人组，可用于研究从头变异。我们还将每年招募至少 10 个 TD 谱系，其中有 4 个或更多受影响的成员，作为基于家族的基因发现的资源。具体目标 2：采用最先进的技术来识别和确认导致 TD 的罕见和常见变异。我们将在 Illumina HumanOmni2.5 -Quad BeadChips 上对样本进行基因分型，以支持拷贝数变异 (CNV) 分析 (Aim 2A) 和全基因组关联研究 (GWAS) (Aim 2B)；全外显子组测序将用于选择、多重影响的 TD 谱系（目标 2C）；我们将在两个时间点使用合并的下一代重测序策略（Aim 2D）对上述研究中确定的最有希望的位点进行跟踪，评估总共 3195 个 EC 和 3195 个匹配对照中的至少 50 个基因；具体目标 3：对 TD 受试者的 300 个转录组进行初步分析，以研究选定的结构和序列变异对顺式、反式和全基因组表达的影响。该项目无需任何费用，将从所有受试者收集 PAXgene 试管，并将其提供给科学界，以便我们小组和其他人进行未来的研究。 公共健康相关性：项目叙述：抽动秽语症 (TD) 是一种人们知之甚少的、常常使人衰弱的神经精神疾病，其特征是持续的发声和运动抽搐，影响全世界千分之三到百分之一的人，主要是儿童。我们的 TD 和其他精神障碍国际专家团队计划招募 5050 名受影响个体，开展全面的基因发现工作，并将收集到的生物材料和临床数据快速提供给广大科学界，从而实现当前和未来的 TD 研究。了解 TD 的原因可能有助于开发新型和改进的治疗方法。