4/7-Collaborative genomic studies of Tourette Disorder

项目摘要/摘要 尽管有强有力的证据表明多发性抽动症(TD)与遗传有关，但在识别Tourette障碍(TD)方面取得的进展 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 确定TD三人组的努力以及我们在自闭症基因组研究方面的非常成功的经验 谱系障碍(ASD)，我们现在已经为可靠的、系统的基因展示了一条明确的前进道路 TD中的发现。我们的TD工作，最近发表在《神经元》杂志上，确定了一个高度自信和 三个可能的TD新风险基因共同指出轴突生长和轴突寻路是潜在的 病理机制1。然而，更重要的是，我们的发现第一次表明， TD患者中过多的从头破坏点突变，其影响大小与我们最近的 ASD的发现。这一发现有力地表明，对较大的队列进行测序将可靠而快速地 导致识别出更多的高渗透性风险基因。此外，我们最近的研究表明， 同时患有TD和TD的先证者中高渗透性损害新生变异体的产量增加 强迫症或注意力缺陷多动障碍，表明我们的努力可能很好 也提供了研究这些经常并存的疾病的遗传风险重叠的途径。我们目前的情况 应用程序建议：(1)将我们特征良好的TD三重队列额外增加1,025个单工三重队列 并使表型数据和生物材料广泛和迅速地提供给广泛的科学 社区；(2)通过基因分型(用于大型新生CNV鉴定)和整体 外显子组测序(用于从头开始的单核苷酸变异体、插入/缺失变异体和小CNV 识别)这些额外的TD三元组，使这些数据也快速和广泛地可用； 长期研究TD生物学的体内和体外基因组学研究进展 开发新的和更有效的治疗策略的目标；和(4)开始对 TD变种使用IPSC来源的神经细胞。考虑到TD本身的潜在衰弱性质，以及 人口流行率约为每100人中有1人，这样的进步将赋予重大的公众 健康福利。研究设计再次在很大程度上依赖于将带来的协作R01机制 与科学家一起在全球多个地点对TD表型有深刻经验，并具有强大的 在罕见的变异人类基因组学和基因发现方面取得成功的记录。具体地说，该提案包括 七个美国主要站点，三个直接分包合同(一个美国站点用于临床监督，两个外国站点 协调站点)，以及欧洲和韩国境内的14个二级临床站点。

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.