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

整合常见和罕见变异来发现与抽动秽语综合征相关的基因 抽动秽语综合征 (TS) 是一种儿童期发病的神经精神疾病，具有高度遗传性 发现明确的 TS 易感基因一直具有挑战性。这个多 PD/PI 应用程序的目标是 鉴定新的 TS 易感基因并检查它们与临床疾病结果的关系， 继续美国抽动秽语协会国际遗传学联盟 (TAAICG) 的工作， 历史最悠久的研究合作小组致力于了解 TS 的遗传原因。 该研究计划包括：1) 对 1,400 名 TS 父母先证者三人组进行全外显子组测序，以识别罕见、 与 TS 相关的潜在有害遗传变异； 2) 从头拷贝数的全基因组分析 这 1,400 个 TS 三重奏中的变异 (CNV)，用于识别与 TS 相关的高影响力、罕见的结构变异； 3) 使用现有全基因组关联研究中有关 TS 相关常见变异的信息 （GWAS）关于 4,819 个 TS 病例和 9,488 个对照的数据，以优先考虑 1,400 个 TS 三人组中的 800 个子集 神秘的结构变异测序研究从头捕获破坏基因的染色体 标准技术无法检测到的重排； 4) 整合已识别的稀有和常见 开发疾病结果的预测模型的变化，包括抽动严重程度、功能障碍、抽动 持续到成年，以及精神共病。 拟议的研究将在马萨诸塞州综合医院、佛罗里达大学、 加州洛杉矶分校和范德比尔特大学医学中心，各自拥有互补的专业知识 计算生物学、下一代测序数据分析以及疾病相关数据的整合 DNA 变异与临床数据。该提案提供了一个独特且令人兴奋的快速推进机会 确定这种复杂且重要的神经精神疾病模型的生物学基础的目标 未来可能会导致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.