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: 8333310
• 负责人: Gary A. Heiman
• 金额: $ 12.13万
• 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/8333310
• 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.

描述（由申请人提供）：摘要/摘要：Tourette障碍（TD）是一种发育性神经精神综合症，其特征是持续的人声和运动综合。虽然最初认为罕见，但现在估计全球流行率为0.3-1％。由于潜在残疾症状以及精神病的合并症率很高，尤其是强迫症（OCD）（OCD）和注意力缺陷多动障碍（ADHD），TD都代表了一个重大的公共卫生问题。尽管有数十年的证据支持了重大的遗传贡献，但识别风险等位基因的进展仍然很慢。这种困难被认为部分是复杂的遗传和实质性遗传和表型异质性的结果。这项合作研究将专门从事TD的国际高度专业临床医生组合在一起，并以统计和分子遗传学家为动机，并以三个中心假设为动机：1）TD基因发现的关键限制因素一直很少公开可用，大型大型，对于许多神经精神疾病而言，现在很常见的种类生物材料资源； 2）基于来自其他许多遗传复杂疾病的最新数据，TD的全面基因组学研究将需要大型样品尺寸，并应集中于稀有和常见等位基因以及序列和结构变体的潜在贡献； 3）对TD的遗传病因的越来越多，将转化为治疗这种经常交织的疾病的新颖，更有效的方法，因此将显着公共健康益处。该应用程序详细阐述了三个特定目标：特定目标1：招募5050个具有TD的人（及其家人），并在收集一年内公开提供DNA，细胞线，cDNA/RNA和表型数据。该样本将包括3195个欧洲高加索（EC）概率的子集； 1250个韩国先证者和3295个亲子三重奏，允许研究从头差异。我们还将每年至少招募10个TD谱系，其中4个或更多受影响的成员作为基于家庭的基因发现的资源。特定目的2：采用最先进的技术来识别并确认对TD造成的稀有和常见变体。我们将在Illumina Handomni2.5 -Quad Beadchips上进行基因型，以支持拷贝数变化（CNV）分析（AIM 2A）和基因组广泛的关联研究（GWAS）（AIM 2B）；整个外显子组测序将用于选择受倍增的TD谱系（AIM 2C）；我们将在两个时间点使用合并的下一代重新测序策略（AIM 2D）在上述研究中确定的最有前途的基因座，评估总共3195 EC和3195个匹配的控件中至少50个基因；特定目的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化对CIS，反式和全基因组表达的含义。如果该项目不付出任何代价，将从所有科目中收集Paxgene管，并将科学界提供给我们小组和其他人的未来研究。