3/7-Collaborative genomic studies of Tourette Disorder

3/7-抽动秽语症的合作基因组研究

• 批准号: 10152699
• 负责人: Alyssa Rosen
• 金额: $ 8.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 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/10152699
• 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.

项目概要 尽管有强有力的证据表明抽动秽语障碍 (TD) 与遗传有关，但在识别抽动秽语障碍方面取得了进展 直到最近，特定的风险基因才被停止。然而，在 NIMH 对我们最初的支持的基础上 确定 TD 三人组的努力以及我们在自闭症基因组研究方面取得的非常成功的经验 谱系障碍（ASD），我们现在已经展示了可靠、系统性基因的清晰前进道路 TD 中的发现。我们的 TD 工作最近发表在《Neuron》杂志上，确定了一项高置信度和三项 可能的新型 TD 风险基因共同表明神经突生长和轴突寻路具有潜力 病理机制1．然而，更重要的是，我们的研究结果首次表明，明显过量 TD 个体中从头开始产生破坏性点突变，其效应大小可与我们最近在 ASD 中的发现相媲美。 这一发现强烈表明，对更大的队列进行测序将可靠且快速地导致 鉴定许多更高渗透性的风险基因。此外，我们最近的工作表明产量增加 患有 TD 和强迫症的先证者中存在高渗透性破坏性新生变异 强迫症或注意力缺陷多动症，这表明我们的努力也可能提供 研究这些经常合并症的遗传风险重叠的途径。我们目前的应用 提议：(1) 通过另外 1,000 个单纯形三重奏来扩展我们良好表征的 TD 三重奏队列，并使 表型数据和生物材料可广泛、快速地提供给广大科学界； (2) 通过基因分型（用于大型从头 CNV 鉴定）和全外显子组测序，加速基因发现 （用于从头单核苷酸变异、插入/缺失变异和小 CNV 鉴定）这些额外的 TD 三人组，使这些数据能够快速、广泛地提供； (3) 延长计算机模拟和体外模拟的过程 基因组学研究阐述 TD 的生物学，长期目标是开发新颖的和更多的 有效的治疗策略； (4) 开始使用 iPSC 衍生的 TD 变体进行生物学表征 神经元细胞。鉴于 TD 本身就可能使人衰弱，并且人口患病率 大约百分之一的人认为，此类进步将带来重大的公共健康益处。研究 设计再次很大程度上依赖于协作 R01 机制，该机制将汇集与 全球多个地点的 TD 表型，科学家在罕见病治疗方面拥有良好的成功记录 变异人类基因组学和基因发现。具体来说，该提案包括七个主要美国站点、四个 直接分包合同（两个美国临床监督和数据分析站点以及两个国外协调站点）， 以及欧洲和韩国境内的十四个二级临床中心。