4/7-Collaborative genomic studies of Tourette Disorder

项目总结/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， 三个可能的新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个体中过量的从头破坏性点突变，其效应大小与我们最近的研究结果相当。 ASD的发现这一发现有力地表明，对较大群体的测序将可靠而快速地进行。 从而鉴定出更多的高外显风险基因。此外，我们最近的研究表明， 在同时患有TD和TD的先证者中， 强迫症或注意力缺陷多动障碍，这表明我们的努力很可能 还提供了研究这些经常合并症的遗传风险重叠的途径。我们目前 申请提出：（1）通过额外的1，025个单纯三人组来扩展我们的充分表征的TD三人组队列 并使表型数据和生物材料广泛和快速地提供给广大的科学家， （2）通过基因分型（用于大的从头CNV鉴定）和整个 外显子组测序（用于从头单核苷酸变异、插入/缺失变异和小CNV 识别）这些额外的TD三人组，使这些数据迅速和广泛提供;（3）扩大 计算机模拟和体外基因组学研究的过程，以长期阐述TD的生物学 开发新的和更有效的治疗策略的目标;和（4）开始生物学表征 使用iPSC衍生的神经元细胞的TD变体。考虑到TD本身的潜在衰弱性质， 人口患病率约为1/100人，这种进步将赋予重大的公众 健康福利。研究设计再次严重依赖于协作R 01机制， 在地球仪的多个研究中心， 在罕见变异人类基因组学和基因发现方面的成功记录。具体而言，该提案包括 七个主要美国研究中心，三个直接分包（一个美国研究中心进行临床监督，两个国外研究中心 协调中心），以及欧洲和韩国的14个二级临床中心。

PROJECT SUMMARY/ABSTRACT 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 1,025 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, three direct subcontracts (one USA site for clinical supervision and two foreign coordinating sites), and fourteen secondary clinical sites within Europe and South Korea.