Integrating Common and Rare Variation to Discover Genes Associated with Tourette Syndrome

综合常见和罕见变异发现抽动秽语综合征相关基因 多发性抽动症(TS)是一种儿童发病的神经精神障碍，具有很高的遗传性 发现明确的TS易感基因一直是具有挑战性的。这个多PD/PI应用程序，其目标是 为了确定TS的新易感基因，并检查它们与临床疾病结局的关系， 继续美国多瑞特协会国际遗传学联合会(TAAICG)的工作， 历史最悠久的研究协作小组，致力于了解TS背后的遗传原因。 研究计划包括：1)对1,400个TS亲本先证者三人组进行外显子组全序列测序，以识别罕见的， 与TS相关的潜在有害遗传变异；2)全基因组新拷贝数分析 这1,400个TS三联体的变异(CNV)，以确定与TS相关的高影响、罕见的结构变异； 3)使用现有全基因组关联研究中有关TS相关共同变异的信息 关于4,819个TS案例和9,488个对照的数据，以确定1,400个TS三元组中800个子集的优先顺序 捕获新基因干扰染色体的隐蔽结构变异测序研究 标准技术无法检测到的重排；以及4)识别的稀有和常见的整合 变异以开发疾病结局的预测模型，包括抽动严重程度、功能障碍、抽动 对成年的坚持，以及精神疾病的共病。 这项拟议的研究将在马萨诸塞州综合医院、佛罗里达大学、华盛顿大学 加州大学洛杉矶分校和范德比尔特大学医学中心，每一个都有互补的专业知识 在计算生物学中，下一代测序数据的分析，以及与疾病相关的集成 DNA变异与临床资料的关系。这一提议提供了一个独特而令人兴奋的机会，可以迅速发展 确定这种复杂而重要的神经精神障碍模型的生物学基础的目标是 未来可能导致对疾病严重程度的预测以及有针对性的治疗和/或预防。

Integrating Common and Rare Variation to Discover Genes Associated with Tourette Syndrome Tourette Syndrome (TS) is a childhood-onset, neuropsychiatric disorder that is highly heritable, though discovery of definitive TS susceptibility genes has been challenging. This multi-PD/PI application, which aims to identify new susceptibility genes for TS and to examine their relationship to clinical disease outcomes, continues the work of the Tourette Association of America International Consortium for Genetics (TAAICG), the longest standing research collaborative group dedicated to understanding the genetic causes underlying TS. The research plan consists of: 1) Whole exome sequencing of 1,400 TS parent-proband trios to identify rare, potentially deleterious genetic variants of relevance to TS; 2) Genome-wide analyses of de novo copy-number variation (CNVs) in these 1,400 TS trios to identify high impact, rare structural variation associated with TS; 3) Use of information about TS-relevant common variation from existing genome-wide association study (GWAS) data on 4,819 TS cases and 9,488 controls to prioritize a subset of 800 of the 1,400 TS trios for cryptic structural variation sequencing studies to capture de novo gene-disrupting chromosomal rearrangements not detectable by standard techniques; and 4) Integration of identified rare and common variation to develop prediction models of disease outcome, including tic severity, functional impairment, tic persistence into adulthood, and psychiatric comorbidity. The proposed study will be conducted at Massachusetts General Hospital, University of Florida, University of California at Los Angeles, and Vanderbilt University Medical Center, each who have complementary expertise in computational biology, analysis of next-generation sequencing data, and integration of disease-associated DNA variation with clinical data. This proposal provides a unique and exciting opportunity to rapidly advance the goal of identifying the biological basis of this complex and important model neuropsychiatric disorder which in the future could lead to prediction of disease severity and to targeted treatments and/or prevention.