Translational phenomics and genomics of Gilles de la Tourette Syndrome

抽动秽语综合征（GTS）是一种常见的、高度遗传的、儿童期发病的神经精神疾病， 以显著的临床异质性和对现有治疗的可变反应为特征的疾病。 这个指导职业发展奖在以病人为导向的研究（K23）的目的是培养 候选人在统计，遗传和临床流行病学方法，使他能够成为一个独立的 转化临床遗传学研究者。该研究计划包括：1）临床 表型分析的目的是使用项目水平的探索性和验证性因素分析来定义同质， 基于GTS的“亚表型”，可以更充分地捕捉不同的临床特征， 疾病; 2）使用遗传性的GTS全基因组关联研究（GWAS）的二次分析 目标1中的亚表型，以鉴定GTS易感性等位基因; 3）培训目标，其中候选人将 参与他的共同导师的试点，随机对照试验的联合行为的选择方面， 治疗和药物治疗GTS获得必要的技能和经验，进行未来的GTS 临床试验，可以结合治疗反应的表型和遗传预测。' 拟定研究将在马萨诸塞州总医院进行，由大卫指导 Pauls博士，GTS表型和遗传研究专家，以及Sabine Wilhelm的共同指导， 博士，GTS治疗研究的专家一群全国公认的导师和顾问， 将在与每个人相关的专门知识领域提供更多的辅导， 研究和培训目标。职业发展计划包括一个教学部分， 哈佛公共卫生学院和哈佛大学心理学系的课程， 研究设计、生物统计学、统计遗传学和临床治疗方法的指导教程。这一综合 研究和培训计划将为未来的多中心药物遗传学研究奠定基础， GTS治疗反应，并将准备候选人提交R 01申请，用于翻译遗传学 GTS和相关疾病的研究。 相关性（参见说明）： 本研究旨在为GTS定义更精确的疾病定义，确定GTS易感基因， 并对研究者进行临床试验方法的培训，使其能够应用这些新的疾病定义， 未来的GTS治疗研究。完成本研究将培养研究者成为领导者 转化研究旨在为GTS患者开发个性化治疗。

Gilles de la Tourette Syndrome (GTS) is a common, highly heritable, childhood-onset neuropsychiatric disorder that is characterized by marked clinical heterogeneity and variable response to existing treatments. The purpose of this Mentored Career Development Award in Patient-Oriented Research (K23) is to train the candidate in statistical, genetic and clinical epidemiologic methods so that he can become an independent investigator in translational, clinical genetic research. The research plan consists of: 1) a clinical phenotyping aim using item-level exploratory and confirmatory factor analysis to define homogeneous, symptom-based GTS "subphenotypes" that may more adequately capture the diverse clinical features of the disease; 2) a secondary analysis of a GTS genome-wide association study (GWAS) using the heritiable subphenotypes in Aim 1 to identify GTS susceptibility alleles; 3) a training aim in which the candidate will participate in selected aspects of his co-mentor's pilot, randomized controlled trial of combined behavioral therapy and pharmacotherapy for GTS to acquire the skills and experience necessary to conduct future GTS clinical trials that can incorporate phenotypic and genetic predictors of treatment response. ' The proposed study will be conducted at Massachusetts General Hospital under the mentorship of David Pauls, Ph.D., an expert in GTS phenotypic and genetic research, and the co-mentorship of Sabine Wilhelm, Ph.D., an expert in GTS treatment research. A group of nationally-recognized mentors and consultants, both local and external, will provide additional mentoring in specialized areas of expertise relevant to each research and training goal. The career development plan includes a didactic component combining coursework at the Harvard School of Public Health and Harvard University Department of Psychology with guided tutorials in study design, biostatistics, statistical genetics, and clinical thals methods. This integrated research and training program will lay the groundwork for future, multi-center pharmacogenetic studies of GTS treatment response and will prepare the candidate to submit an R01 application for translational genetic studies of GTS and related disorders. RELEVANCE (See instructions): This research aims to define more precise disease definitions for GTS, to identify GTS susceptibility genes, and to train the investigator in clinical trials methods so that he can apply these novel disease definitions and genes to future GTS treatment studies. Completion of this study will train the investigator to become a leader in translational research aimed at developing personalized treatments for GTS patients.