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.

项目总结 尽管有强有力的证据表明多发性抽动症(TD)与遗传有关，但在识别Tourette障碍(TD)方面取得的进展 直到最近，特定的风险基因一直处于停滞状态。然而，基于NIMH对我们最初的支持 确定TD三人组的努力以及我们在自闭症基因组研究方面的非常成功的经验 谱系障碍(ASD)，我们现在已经为可靠的、系统的基因展示了一条明确的前进道路 TD中的发现。我们的TD研究，最近发表在《神经元》杂志上，确定了一个高度自信和三个 可能的新TD风险基因共同指向轴突生长和轴突寻路的可能性 病理机制1。然而，更重要的是，我们的发现第一次显示出明显的过剩 在TD患者中，从头开始破坏性点突变的数量，其影响大小与我们最近在ASD上的发现相媲美。 这一发现有力地表明，对更大的队列进行测序将可靠而快速地导致 更多高渗透性风险基因的鉴定。此外，我们最近的研究表明，产量增加 同时患有TD和强迫症的先证者中高渗透性损害从头基因变异的研究 强迫症或注意力缺陷多动障碍，这表明我们的努力很可能也会提供 研究这些经常并存的疾病的遗传风险重叠的途径。我们当前的应用程序 建议：(1)将我们的TD三重奏队伍再增加1,000个单工三重奏，并使 广泛和迅速地向广大科学界提供表型数据和生物材料；(2) 通过基因分型(用于大片段新生CNV鉴定)和整个外显子组测序，加速基因发现 (对于从头开始的单核苷酸变异体、插入/缺失变异体和小CNV识别) TD三人组，使这些数据也迅速和广泛地获得；(3)扩展了在硅和体外的过程 基因组学研究阐述TD生物学，长期目标是开发新的和更多的 有效的治疗策略；以及(4)开始使用IPSC衍生的TD变种的生物学特性 神经细胞。鉴于TD本身的潜在衰弱性质，以及人口流行 大约每100个人中就有一个人，这样的进步将带来显著的公共卫生利益。这项研究 设计再次在很大程度上依赖于协作R01机制，该机制将与 全球多个地点的TD表型与科学家在罕见疾病中取得成功的良好记录 变异人类基因组学和基因发现。具体地说，该提案包括七个美国主要地点，四个 直接分包合同(两个美国临床监督和数据分析站点和两个外国协调站点)， 以及欧洲和韩国境内的14个二级临床站点。