3/7-Administrative Supplement due to COVID-19 Impact to Collaborative genomic studies of Tourette Disorder

3/7-由于 COVID-19 对抽动秽语症协作基因组研究的影响而作出的行政补充

• 批准号: 10598794
• 负责人: Alyssa Rosen
• 金额: $ 16.48万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598794
• 关键词: Administrative Supplement; Affect; Attention deficit hyperactivity disorder; Biocompatible Materials; Biological; Biology; COVID-19 impact; Cells; Child; Clinical Data; Code; Collaborations; Communities; Copy Number Polymorphism; Data; Data Analyses; Development; Disease; Europe; Family; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Gilles de la Tourette syndrome; Goals; Health Benefit; In Vitro; Individual; International; Investigation; Lead; Molecular; Motor Tics; National Institute of Mental Health; Nature; Neurites; Neurons; Parents; Pathologic; Peptide Sequence Determination; Persons; Phenotype; Point Mutation; Population; Prevalence; Process; Public Health; Publishing; Recording of previous events; Recurrence; Reporting; Research Design; Research Project Grants; Rest; Scientist; Site; South Korea; Supervision; Time; Variant; Vocal Tics; Work; autism spectrum disorder; axonal pathfinding; clinical research site; cohort; comorbidity; de novo mutation; disorder risk; effective therapy; exome sequencing; experience; gene discovery; genomic data; genomic locus; human genomics; in silico; induced pluripotent stem cell; neuropsychiatric disorder; novel; phenotypic data; proband; psychiatric genomics; rare variant; recruit; risk variant; success; treatment strategy; Administrative Supplement; Affect; Attention deficit hyperactivity disorder; Biocompatible Materials; Biological; Biology; COVID-19 impact; Cells; Child; Clinical Data; Code; Collaborations; Communities; Copy Number Polymorphism; Data; Data Analyses; Development; Disease; Europe; Family; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Gilles de la Tourette syndrome; Goals; Health Benefit; In Vitro; Individual; International; Investigation; Lead; Molecular; Motor Tics; National Institute of Mental Health; Nature; Neurites; Neurons; Parents; Pathologic; Peptide Sequence Determination; Persons; Phenotype; Point Mutation; Population; Prevalence; Process; Public Health; Publishing; Recording of previous events; Recurrence; Reporting; Research Design; Research Project Grants; Rest; Scientist; Site; South Korea; Supervision; Time; Variant; Vocal Tics; Work; autism spectrum disorder; axonal pathfinding; clinical research site; cohort; comorbidity; de novo mutation; disorder risk; effective therapy; exome sequencing; experience; gene discovery; genomic data; genomic locus; human genomics; in silico; induced pluripotent stem cell; neuropsychiatric disorder; novel; phenotypic data; proband; psychiatric genomics; rare variant; recruit; risk variant; success; treatment strategy

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 Neuron and in Cell Reports, identified two high confidence and three probable novel TD risk genes, and collectively, pointed to neurite outgrowth and axon pathfinding as potential pathological mechanisms5,6. More importantly, however, our findings demonstrated, for the first time, a clear excess of de novo damaging point mutations and copy number variants (CNV) 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 OCD or ADHD, 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 and locus discovery, via whole exome sequencing (to identify rare and/or de novo sequence variants) and genotyping (to identify rare and/or de novo CNVs) of these additional TD trios, making these data rapidly and widely available as well (e.g., we have a long history of sharing our genotyping data with the Psychiatric Genomics Consortium or PGC1 in order to facilitate common variant studies of TD and related disorders); (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 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 and collaboration 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 努力确定TD三重奏以及我们在自闭症基因组研究方面非常成功的经验 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。我们最近在神经元和细胞报告中发表的TD工作确定了两个高信心 以及三个有问题的新型TD风险基因，共同指出神经蛋白的生长和轴突探索 潜在的病理机制5,6。但是，更重要的是，我们的发现首次证明了 在患有TD的个体中，明确超过了从头损害点突变和拷贝数变体（CNV）， 效果大小，以使我们最近在ASD中的发现有风险。这一发现强烈表明较大的测序 队列将可靠，迅速地导致鉴定许多高度渗透性的风险基因。而且， 我们最近的工作表明，在可能是高度渗透性破坏性变种中的产量提高了。 受TD和OCD或ADHD的影响，这表明我们的努力也很可能提供了研究的途径 在这些经常发生的情况下，遗传风险重叠。我们当前的申请建议：（1）扩展我们的 TD三重奏队列的表征良好。 广泛的科学界的生物材料广泛并迅速使用； （2）加速基因和基因座 通过整个外显子组测序（识别稀有和/或从头序列变体）和基因分型（TO TO TO）发现 确定这些额外的TD三重奏的稀有和/或从头cnvs），使这些数据迅速且广泛可用 同样（例如，我们有悠久的历史，可以与精神病基因组学联盟共享基因分型数据 或PGC1，以促进TD和相关疾病的常见变体研究）； （3）扩展了In的过程 硅和体外基因组学研究以阐述TD的生物学，其长期目标的发展 新颖，更有效的治疗策略； （4）使用使用TD变体的生物学表征 IPSC衍生的神经元细胞。鉴于单独的TD的性质使人衰弱，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，科学家的成功记录很强， 稀有人类基因组学和基因发现的合作。具体而言，该提案包括七个 美国初级站点，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，两个 外国协调地点）和欧洲和韩国境内的14个次要临床场所。