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

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抽动秽语障碍（TD）的遗传贡献，但在识别 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， 努力确定TD三重奏以及我们在自闭症基因组研究方面的高度成功经验 谱系障碍（ASD），我们现在已经证明了一条明确的道路，可靠的，系统的基因 发现TD我们的TD工作最近发表在Neuron和Cell Reports上，确定了两个高置信度 和三个可能的新的TD风险基因，并共同指出，神经突生长和轴突寻路， 潜在的病理机制5，6.然而，更重要的是，我们的研究结果首次证明， TD个体中存在明显过量的从头破坏性点突变和拷贝数变异（CNV）， 与我们最近在ASD中的发现相媲美的效应大小。这一发现有力地表明， 群组将可靠和快速地导致许多更高渗透风险基因的鉴定。此外，委员会认为， 我们最近的研究表明，在先证者中， 同时受TD和OCD或ADHD影响，这表明我们的努力也可能提供研究 这些经常合并的疾病的遗传风险重叠。我们的当前申请提出：（1）扩展我们的 通过额外的1,000个单纯三人组对TD三人组队列进行良好表征，并获得表型数据， 生物材料广泛和迅速提供给广大的科学界;（2）加速基因和基因座 通过全外显子组测序（以鉴定罕见和/或从头序列变体）和基因分型（以 鉴定这些额外TD三联体的罕见和/或从头CNVs），使这些数据快速和广泛可用 同样（例如，我们与精神病学基因组学联盟分享基因分型数据的历史由来已久 或PGC 1，以促进TD和相关疾病的常见变异研究）;（3）延长在 计算机和体外基因组学研究，以阐述TD的生物学，长期目标是开发 新的和更有效的治疗策略;和（4）开始TD变体的生物学表征， iPSC衍生的神经元细胞。考虑到TD本身的衰弱性质，以及 大约每100人中有1人，这种进步将带来重大的公共卫生效益。研究 设计再次在很大程度上依赖于协作R 01机制，该机制将把深度经验与 TD表型在地球仪的多个地点与科学家有良好的成功记录， 在罕见变异人类基因组学和基因发现方面的合作。具体而言，该提案包括七项 主要美国研究中心，四个直接分包（两个美国研究中心用于临床监督和数据分析，两个 国外协调中心）和欧洲和韩国的14个二级临床中心。