Acceleration of risk gene discovery for Tic Disorders through large-scale collaboration

项目摘要 抽动秽语综合征（TS）是一种复杂的神经精神疾病，其特征是持续的不受控制的 运动和言语抽搐如果病人只有身体或语言抽搐，但不是两者兼而有之，他们反而会得到诊断 慢性抽动障碍（CTD）两者都可以严重抑制患者的生活质量和生计。有很长的- 长期流行病学证据表明，TS和CTD是家族内聚集的遗传性疾病。 当代的遗传学研究主要集中在共同的变异上， 与此，但还没有提供大量的洞察力，关于生物学的基础上，这些条件。研究 使用全外显子组测序（WES）的罕见编码变异能够检测单个风险基因， 会大大增加风险。目前，只有三个中型TS/CTD WES 发表的研究，但都强烈支持罕见的编码变异对这种情况的贡献。不幸的是， 然而，汇总这三项研究后的总样本量远远落后于其他神经精神病学研究。 自闭症谱系障碍和精神分裂症等病症。尽管TS/CTD是 常见的致残性和高度遗传性疾病在本提案中，我们描述了一种具有成本效益的战略， 通过利用来自油井的现有DNA样本，显著增加TS/CTD WES分析的样本量， 已表征的TS/CTD病例和来自TS/CTD病例和对照的现有WES数据集， 纳入TS/CTD研究。具体来说，我们提出了一个非常可行的两年期研究，最终将增加两倍， 总TS/CTD病例WES样本量和加速风险基因发现。我们将首先生成新的WES 来自瑞典的140例TS/CTD三人组和160例单例患者的数据，所有患者均进行了深度表型分析。这些 然后将数据与来自1474例TS/CTD病例和15，200例对照的尚未发表的WES数据相结合。 接下来，我们将把我们的数据集与上述三项已发表研究的所有WES数据进行整合， 以产生最大可能的样本（1042个三人组，1634个病例和15，200个对照）。这将最大限度地提高功率 进行一项旨在发现高风险基因的荟萃分析。我们的综合性稀有变种 分析还将包括TS/CTD常见多基因风险的测量以及丰富的临床数据。这 将使我们开始检查罕见和常见变异是否相互作用，影响有意义的临床 结果，如对行为治疗的反应。最后，我们将创建一个集中的在线资源， 促进全世界共享源代码、质量控制指标和基于基因的汇总统计数据 TS/CTD WES数据。我们的目标是促进其他TS/CTD研究人员的工作，以加速基因发现 为这个未被充分研究的条件。

PROJECT SUMMARY Tourette Syndrome (TS) is a complex neuropsychiatric condition that is characterized by persistent uncontrolled motor and verbal tics. If a patient only has physical or verbal tics but not both, they instead receive a diagnosis of Chronic Tic Disorder (CTD). Both can severely inhibit a patients’ quality of life and livelihood. There is long- standing epidemiological evidence for TS and CTD being heritable conditions that cluster within families. Contemporary genetic studies largely focused on common variation have produced results that are consistent with this, but have not provided a great deal of insight regarding the biology underlying these conditions. Studies of rare coding variation using whole exome sequencing (WES) enable the detection of individual risk genes that when perturbed can substantially increase risk. Currently, there are just three modestly-sized TS/CTD WES studies published, but all strongly support the contribution of rare coding variants to this condition. Unfortunately, however, the total sample size after aggregating these three studies lags well behind other neuropsychiatric conditions such as autism spectrum disorder and schizophrenia. This is despite the fact that TS/CTD are common, disabling and highly heritable conditions. In this proposal, we describe a cost-efficient strategy to markedly increase samples size for TS/CTD WES analyses by capitalizing on existing DNA samples from well- characterized TS/CTD cases and existing WES datasets from TS/CTD cases and controls that have yet to be included in TS/CTD studies. Specifically, we propose a highly feasible two-year study that would ultimately triple the total TS/CTD case WES sample size and accelerate risk gene discovery. We will first generate new WES data for 140 TS/CTD trios and 160 singleton cases from Sweden, all of whom are deeply phenotyped. These data will then be combined with as-yet unpublished WES data from 1474 TS/CTD cases and 15,200 controls. Next, we will integrate our dataset with all WES data from the three published studies mentioned above in order to generate the largest possible sample (1042 trios, 1634 cases and 15,200 controls). This will maximize power for a meta-analysis geared toward high-confidence risk gene discovery. Our comprehensive rare variant analyses will also incorporate measures of common polygenic risk for TS/CTD as well as rich clinical data. This will allow us to begin to examine whether rare and common variation interact to influence meaningful clinical outcomes such as response to behavioral treatment. Finally, we will create a centralized online resource to facilitate the sharing of source code, quality control metrics and gene-based summary statistics for all worldwide TS/CTD WES data. Our goal is to facilitate the work of other TS/CTD researchers to accelerate gene discovery for this understudied condition.