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

通过大规模合作加速抽动症风险基因的发现

• 批准号: 10726443
• 负责人: Matthew Halvorsen
• 金额: $ 42.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726443
• 关键词: Acceleration; Behavior Therapy; Biology; Child; Chronic; Clinic; Clinical; Clinical Data; Code; Collaborations; Complex; DNA; Data; Data Analyses; Data Set; Detection; Diagnosis; Disease; Distress; Dizygotic Twins; Emotional; Epidemiology; Equity; Etiology; FDA approved; Family; First Degree Relative; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomics; Gilles de la Tourette syndrome; Goals; Heritability; High Prevalence; Individual; Intelligence; Measures; Meta-Analysis; Molecular Target; Monozygotic twins; Motor; Movement; Muscle; Neurodevelopmental Disorder; Open Reading Frames; Outcome; Parents; Patient-Focused Outcomes; Patients; Phenotype; Population; Prevalence; Process; Publishing; Quality Control; Quality of life; Recurrence; Reproducibility; Research; Research Personnel; Resources; Risk; Route; Sample Size; Sampling; Schizophrenia; Severities; Source Code; Suicide; Sweden; Tic disorder; Transient Tics; Variant; Work; aged; autism spectrum disorder; cost effective; cost efficient; disorder risk; exome sequencing; gene discovery; genetic testing; genetic variant; genome wide association study; individualized medicine; insight; neuropsychiatry; new therapeutic target; novel; novel therapeutics; online resource; proband; rare variant; recruit; response; risk variant; side effect; statistics; substance misuse; therapeutic development; verbal; vocalization; Acceleration; Behavior Therapy; Biology; Child; Chronic; Clinic; Clinical; Clinical Data; Code; Collaborations; Complex; DNA; Data; Data Analyses; Data Set; Detection; Diagnosis; Disease; Distress; Dizygotic Twins; Emotional; Epidemiology; Equity; Etiology; FDA approved; Family; First Degree Relative; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomics; Gilles de la Tourette syndrome; Goals; Heritability; High Prevalence; Individual; Intelligence; Measures; Meta-Analysis; Molecular Target; Monozygotic twins; Motor; Movement; Muscle; Neurodevelopmental Disorder; Open Reading Frames; Outcome; Parents; Patient-Focused Outcomes; Patients; Phenotype; Population; Prevalence; Process; Publishing; Quality Control; Quality of life; Recurrence; Reproducibility; Research; Research Personnel; Resources; Risk; Route; Sample Size; Sampling; Schizophrenia; Severities; Source Code; Suicide; Sweden; Tic disorder; Transient Tics; Variant; Work; aged; autism spectrum disorder; cost effective; cost efficient; disorder risk; exome sequencing; gene discovery; genetic testing; genetic variant; genome wide association study; individualized medicine; insight; neuropsychiatry; new therapeutic target; novel; novel therapeutics; online resource; proband; rare variant; recruit; response; risk variant; side effect; statistics; substance misuse; therapeutic development; verbal; vocalization

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.

项目摘要 Tourette综合征（TS）是一种复杂的神经精神疾病，其特征是持续不受控制 马达和言语抽动。如果患者只有身体或言语抽搐，但两者都不是两者，则可以接受诊断 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 TS和CTD的常规流行病学证据是聚集在家庭中的可遗传条件。 当代遗传研究主要集中在共同变异上，产生了一致的结果 这样，但没有提供有关这些条件为基础的生物学的大量见解。研究 使用整个外显子组测序（WES）的稀有编码变化，使人可以检测单个风险基因 当扰动时，可以大大增加风险。目前，只有三个适度的TS/CTD WES 研究发表了，但都强烈支持稀有编码变体对这种情况的贡献。很遗憾， 但是，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 自闭症谱系障碍和精神分裂症等疾病。这是TS/CTD的事实 常见，残疾和高度遗传的条件。在此提案中，我们描述了一种经济高效的策略 通过利用来自良好的现有DNA样品的利用，明显增加了TS/CTD WES分析的样品大小 TS/CTD案例和现有的WES数据集从TS/CTD案例和对照中进行了表征 TS/CTD研究。具体而言，我们提出了一项高度可行的两年研究，最终将三倍 TS/CTD总体情况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 TS/CTD三重奏和160个单例案例的数据，所有这些案例都深入表型。这些 然后，数据将与来自1474 TS/CTD案例和15200个对照的尚未发表的WES数据合并。 接下来，我们将将数据集与上面提到的三项已发表研究的所有WES数据集成 为了生成最大的样本（1042个三重奏，1634例和15,200个对照）。这将最大化力量 用于旨在高信任风险基因发现的荟萃分析。我们全面的稀有变体 分析还将纳入TS/CTD的常见多基因风险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以影响有意义的临床 结果，例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 促进全球范围内的源代码，质量控制指标和基于基因的摘要统计数据的共享 TS/CTD WES数据。我们的目标是促进其他TS/CTD研究人员加速基因发现的工作 对于这种理解的条件。