4/7-Collaborative genomic studies of Tourette Disorder

4/7-抽动秽语症的合作基因组研究

• 批准号: 10159309
• 负责人: DONALD L GILBERT
• 金额: $ 11.93万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-10 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159309
• 关键词: Affect; Asians; Attention deficit hyperactivity disorder; Biocompatible Materials; Biological; Biology; Brain; C2 Domain; Cell model; Cells; Child; Clinical; Clinical Data; Code; Communities; Copy Number Polymorphism; Data; Data Analyses; Development; Dimensions; Ensure; Europe; Family; Family Study; Foundations; Funding; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Gilles de la Tourette syndrome; Goals; Health Benefit; Human; In Vitro; Individual; International; Investigation; Journals; Lead; Link; Methods; Molecular; Motor Tics; National Institute of Mental Health; Nature; Neurites; Neurons; Obsessive-Compulsive Disorder; Parents; Pathologic; Peptide Sequence Determination; Phenotype; Point Mutation; Population; Prevalence; Process; Public Health; Publishing; Recurrence; Reporting; Research Design; Research Personnel; Research Project Grants; Rest; Sampling; Science; Scientist; Single Nucleotide Polymorphism; Site; Source; South Korea; Structure; Supervision; Testing; Time; Variant; Vocal Tics; Work; autism spectrum disorder; axonal pathfinding; base; biological systems; clinical research site; cohort; comorbidity; de novo mutation; disorder risk; effective therapy; exome sequencing; experience; functional genomics; gene discovery; genomic data; genomic locus; human genomics; in silico; induced pluripotent stem cell; induced pluripotent stem cell technology; insertion/deletion mutation; multidimensional data; neuropsychiatric disorder; novel; phenotypic data; proband; rare variant; recruit; risk variant; success; treatment strategy; variant detection

PROJECT SUMMARY Despite strong evidence for a genetic contribution to Tourette disorder (TD), progress in the identification of specific risk genes has been, until quite recently, halting. However, building upon NIMH's support for our initial efforts to ascertain TD trios as well as our highly successful experience with genomic investigations of autism spectrum disorders (ASD), we have now demonstrated a clear path forward for reliable, systematic gene discovery in TD. Our TD work, recently published in the journal Neuron, identified one high confidence and three probable novel TD risk genes collectively pointing to neurite outgrowth and axon pathfinding as potential pathological mechanisms1. More importantly, however, our findings demonstrate, for the first time, a clear excess of de novo damaging point mutations in individuals with TD, with effect sizes that rival our recent findings in ASD. This discovery strongly suggests that sequencing of larger cohorts will reliably and rapidly lead to the identification of many more highly penetrant risk genes. Moreover, our recent work suggests an increased yield of highly penetrant damaging de novo variants in probands who are affected both with TD and obsessive compulsive disorder or attention deficit hyperactivity disorder, suggesting that our efforts may well also offer avenues to study the overlap in genetic risks for these often-comorbid conditions. Our current application proposes to: (1) expand our well characterized TD trio cohort by an additional 1,000 simplex trios and make the phenotypic data and biological materials widely and rapidly available to the broad scientific community; (2) accelerate gene discovery, via genotyping (for large de novo CNV identification) and whole exome sequencing (for de novo single nucleotide variant, insertion/deletion variant, and small CNV identification) of these additional TD trios, making these data rapidly and widely available as well; (3) extend the process of in silico and in vitro genomics investigations to elaborate the biology of TD with the long term goal of developing novel and more effective treatment strategies; and (4) begin biological characterization of TD variants using iPSC-derived neuronal cells. Given the potentially debilitating nature of TD alone, and a population prevalence of approximately 1 in 100 individuals, such advances would confer a significant public health benefit. The study design again rests heavily on the collaborative R01 mechanism that will bring together deep experience with the TD phenotype at multiple sites across the globe with scientists with a strong track record of success in rare variant human genomics and gene discovery. Specifically, the proposal includes seven primary US sites, four direct subcontracts (two USA sites for clinical supervision and data analysis and two foreign coordinating sites), and fourteen secondary clinical sites within Europe and South Korea.

项目摘要 尽管有强有力的证据表明对图雷氏障碍（TD）有遗传贡献，但在鉴定方面的进展 直到最近，特定的风险基因一直停止。但是，基于NIMH对我们最初的支持 确定TD三重选以及我们在自闭症基因组研究方面的非常成功的经验的努力 频谱障碍（ASD），我们现在已经为可靠的，系统的基因展示了一条明确的路径 TD中的发现。我们最近发表在《神经元期刊》上的TD工作确定了一个高信心和三个 可能的新型TD风险基因共同指向神经突生长和轴突探测潜力 病理机制1。但是，更重要的是，我们的发现首次证明了明显的多余 TD个体中从头损害点突变的作用大小，与我们最近在ASD中的发现相媲美。 这一发现强烈表明，较大队列的测序将可靠，迅速导致 鉴定许多更高的渗透风险基因。此外，我们最近的工作表明产量增加 在受到TD和痴迷的影响的探针中，高渗透性损害的从头变体 强迫症或注意力缺陷多动障碍，表明我们的努力也很可能提供 研究这些经常刺激性条件的遗传风险重叠的途径。我们当前的应用程序 提议：（1）通过另外1,000个单纯三重奏扩展我们良好的TD三重奏队列 广泛的科学界广泛且迅速地使用表型数据和生物材料； （2） 通过基因分型（用于大型新CNV识别）和整个外显子组测序加速基因发现 （对于从头单核苷酸变体，插入/缺失变体和小的CNV识别） TD三重奏，使这些数据迅速且广泛可用； （3）扩展硅和体外的过程 基因组学调查以阐述TD的生物学，其长期目标是开发新颖的和更多的 有效的治疗策略； （4）使用IPSC衍生的TD变体开始生物学表征 神经元细胞。鉴于单独使用TD的潜在使人衰弱的性质，并且人口流行率 大约有100个人中有1个人将带来重大的公共卫生益处。研究 设计再次取决于协作R01机制，该机制将与 在全球多个地点的TD表型，科学家在稀有方面拥有良好的成功记录 变体人类基因组学和基因发现。具体而言，该提案包括七个主要网站，四个 直接分包合同（两个用于临床监督和数据分析的美国站点以及两个外国协调站点）， 以及欧洲和韩国的14个次要临床场所。