2/7-Collaborative genomic studies of Tourette Disorder

2/7-抽动秽语症的合作基因组研究

基本信息

批准号：
10397559
负责人：
MATTHEW W. STATE
金额：
$ 82.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-27 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397559
关键词：
Affect Asian 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 Persons 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

项目摘要

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.

项目摘要尽管有强烈的遗传贡献图形障碍（TD）的证据，但鉴定的进展但是，直到最近，特定的风险基因一直停止。确定TD三重奏以及我们对自闭症基因组研究的经验的努力频谱障碍（ASD），我们现在已经为可靠的，系统的Genee展示了一条清晰的途径 TD中的发现。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，我们的发现首次证明了 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。这种发现强烈表明，较大的队列的测序将迅速纳入此外，我们最近的工作表明了许多高度渗透风险基因。高度渗透性损害的从头变体是曾经是曾经的属于和痴迷的事物强迫障碍或注意力缺陷多动障碍，表明我们的TO也可能会提供在我们当前的应用中，研究遗传风险重叠的途径提议：（1）扩展我们良好的TD三重奏队列，再增加1,000个单纯的三重奏，并使其成为广泛的科学界广泛使用的表型数据和生物材料；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，使数据迅速且广泛可用；基因组学调查详细阐述了TD，其长期目标是开发新颖和更多有效的治疗策略；神经元细胞。大约有100个人中有1个，WOWLD赋予了重大的公共卫生益处设计再次取决于协作R01机制，该机制将带来深厚的体验罕见的多个站点的TD表型人类基因组学和基因发现。直接分包合同（两个用于临床监督和数据分析的美国站点，两个外国排列地点），欧洲和韩国内有14个次要临床。