6/8-Collaborative genomic studies of Tourette Disorder

6/8-抽动秽语症的合作基因组研究

• 批准号: 8608700
• 负责人: DOROTHY E GRICE
• 金额: $ 7.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608700
• 关键词: Collaborative; genomic; studies; Tourette; Disorder

DESCRIPTION (provided by applicant): Tourette Disorder (TD) is a developmental neuropsychiatric syndrome characterized by the combination of persistent vocal and motor tics. While initially considered rare, the world-wide prevalence is now estimated to be 0.3-1 percent. Both as a consequence of potentially disabling symptoms as well as very high rates of psychiatric co-morbidity, particularly with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), TD represents a significant public health concern. Despite decades of evidence supporting a significant genetic contribution, progress on the identification of risk alleles has been disappointing. This difficulty is thought be, in part, a consequence of complex inheritance as well as substantial genetic and phenotypic heterogeneity. This collaborative application unites a group of expert clinicians specializing in Tourette Disorder (TD) with statistical and molecular geneticists who are motivated by three pressing concerns: 1) That a key rate-limiting factor for TD gene discovery has been the paucity of publicly available, large-scale biomaterial resources of the kind that are now commonplace for many neuropsychiatric disorders; 2) that to be successful, genetics efforts in TD must focus on the contribution of both DNA sequence and structural variation, and both rare and common alleles in large sample populations; and 3) that an increased understanding of the genetic etiology of TD will ultimately translate into novel and more effective approaches to treating this often-debilitating disorder, and consequently will have marked public health benefits. Given these concerns, the application elaborates three specific aims: Specific Aim 1 supports an ongoing collaboration of 7 US and 2 international clinical sites that will result in the recruitment of 4450 individuals with TD over five years. This cohort will include a subset of 2995 parent-child trios, allowing for evaluation of de novo DNA sequence and structural variation. This sample will be made rapidly available to the broad scientific community. Specific Aim 2 will support simultaneous copy number variation (CNV) and genome wide association studies (GWAS) on this cohort. In addition, a next-generation, deep re-sequencing effort is proposed to confirm the relevance of two high priority biological pathways identified in the preliminary studies as well as to follow-up on the most promising transcripts that will emerge from the CNV, SNP and gene expression studies proposed herein. Finally, Specific Aim 3 extends a NIH-funded, exploratory project to analyze the transcriptomes of TD subjects and will collect, freeze and store PAXgene tubes on all subjects to enable future gene expression studies and to become part of the publically available NIMH Center resource. In addition, gene expression analyses will be performed on 300 affected subjects shown to have "high priority" CNVs, investigating the implications of structural variation for cis, trans and genome-wide expression.

描述(申请人提供)：多发性抽动障碍(TD)是一种以持续性发声和运动痉挛为特征的发育性神经精神综合征。虽然最初被认为是罕见的，但现在世界范围内的流行率估计为0.3%-1%。由于潜在的致残症状以及精神疾病的高共患率，特别是强迫症(OCD)和注意力缺陷多动障碍(ADHD)，TD是一个重大的公共卫生问题。尽管几十年来的证据支持重大的遗传贡献，但在识别风险等位基因方面的进展一直令人失望。这一困难被认为部分是复杂遗传以及大量遗传和表型异质性的结果。这种协作应用程序将一组专门研究多发性抽动症(TD)的专家临床医生与统计和分子遗传学家联合起来，他们的动机是三个紧迫的问题：1)TD基因发现的一个关键限制因素是缺乏公开可用的大规模生物材料资源，这种资源现在对许多神经精神疾病来说是司空见惯的；2)为了取得成功，TD的遗传学努力必须专注于DNA序列和结构变异以及大样本人群中稀有和常见的等位基因的贡献；3)对TD的遗传病因的更多了解最终将转化为治疗这种经常使人虚弱的疾病的新的、更有效的方法，因此将对公众健康产生显著的好处。鉴于这些担忧，该申请详细阐述了三个具体目标：特定目标1支持7个美国和2个国际临床站点的持续合作，这将导致在5年内招募4450名TD患者。这个队列将包括2995个亲子三元组的子集，允许评估从头DNA序列和结构变异。该样本将迅速提供给广大科学界。特定目标2将支持该队列的同步拷贝数变异(CNV)和全基因组关联研究(GWAS)。此外，下一代，深入的重新测序工作被提出，以确认在初步研究中确定的两个高优先级生物通路的相关性，以及对将从这里提出的CNV、SNP和基因表达研究中出现的最有希望的转录本的后续工作。最后，SPICAL AIM 3扩展了一个由NIH资助的探索性项目，用于分析TD受试者的转录本，并将收集、冷冻和存储所有受试者的PAX基因管，以支持未来的基因表达研究，并成为公共可用的NIMH中心资源的一部分。此外，还将对300名被证明具有“高优先级”CNV的受影响受试者进行基因表达分析，调查结构变异对顺式、反式和全基因组表达的影响。