Translational phenomics and genomics of Gilles de la Tourette Syndrome

Gilles de la Tourette综合征(GTS)是一种常见的、高度可遗传的儿童期起病的神经精神障碍，其特征是显著的临床异质性和对现有治疗的不同反应。这个以患者为中心的研究指导职业发展奖(K23)的目的是培训候选人在统计、遗传学和临床流行病学方法方面的培训，使他能够成为翻译和临床遗传学研究的独立研究员。研究计划包括：1)临床表型目标，使用项目级探索性和验证性因素分析来定义同质的、基于症状的GTS“亚型”，这可能更充分地反映疾病的不同临床特征；2)使用目标1中可遗传的亚型对GTS全基因组关联研究进行二次分析，以确定GTS的易感等位基因；3)培训目标，其中候选人将参加他的共同导师的联合行为疗法和药物疗法的试点、随机对照试验的选定方面，以获得进行未来GTS临床试验所需的技能和经验，这些临床试验可以纳入治疗反应的表型和遗传预测因素。‘这项拟议的研究将在马萨诸塞州总医院进行，由GTS表型和基因研究专家David Pauls博士指导，GTS治疗研究专家Sabine Wilhelm博士共同指导。一组国家认可的当地和外部导师和顾问将在与每个研究和培训目标相关的专门知识领域提供额外的辅导。职业发展计划包括一个教学部分，将哈佛公共卫生学院和哈佛大学心理学系的课程与研究设计、生物统计学、统计遗传学和临床TALS方法的指导教程结合起来。这一综合研究和培训计划将为未来GTS治疗反应的多中心药物遗传学研究奠定基础，并将准备候选人提交GTS和相关疾病的翻译遗传学研究的R01申请。相关性(参见说明)：这项研究旨在为GTS定义更精确的疾病定义，识别GTS易感基因，并在临床试验方法方面培训研究人员，以便他能够将这些新的疾病定义和基因应用于未来的GTS治疗研究。这项研究的完成将使研究人员成为旨在为GTS患者开发个性化治疗的转化研究的领导者。

DESCRIPTION (provided by applicant): 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.