7/7-Collaborative genomic studies of Tourette Disorder

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《神经元》杂志上，确定了一个高置信度和三个 可能的新型TD风险基因共同指向神经突生长和轴突寻路作为潜在的 病理机制1.然而，更重要的是，我们的研究结果首次表明， TD个体的从头破坏性点突变，其效应大小与我们最近在ASD中的发现相媲美。 这一发现有力地表明，对较大队列的测序将可靠而快速地导致对大规模群体的测序。 识别出更多的高外显风险基因。此外，我们最近的研究表明， 高渗透破坏性的从头变异的先证者谁是受TD和强迫症 强迫症或注意力缺陷多动障碍，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 建议：（1）通过额外的1，000个简单的三人组来扩展我们的TD三人组队列，并使 表型数据和生物材料广泛和迅速地提供给广大科学界;（2） 通过基因分型（用于大的从头CNV鉴定）和全外显子组测序加速基因发现 (for从头单核苷酸变异、插入/缺失变异和小CNV鉴定）。 TD trios，使这些数据快速和广泛提供，以及（3）扩展的过程中，在电脑和体外 基因组学研究，阐述TD的生物学，长期目标是开发新的和更多的 有效的治疗策略;和（4）开始使用iPSC衍生的TD变体的生物学表征。 神经元细胞考虑到TD本身的潜在致弱性，以及 大约每100个人中就有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 在地球仪的多个地点进行TD表型研究，科学家在罕见的 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（两个美国临床监督和数据分析中心和两个国外协调中心）， 以及欧洲和韩国的14个二级临床研究中心。

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.