6/8-Collaborative genomic studies of Tourette Disorder

描述（由申请人提供）：图雷特障碍（TD）是一种发展性神经精神综合征，其特征是持续的声音和运动抽搐。虽然最初被认为是罕见的，但现在全球流行率估计为0.3% - 1%。由于潜在的致残症状以及非常高的精神合并症发病率，特别是强迫症（OCD）和注意力缺陷多动障碍（ADHD）， TD代表了一个重大的公共卫生问题。尽管几十年来有证据支持重要的遗传贡献，但在识别风险等位基因方面的进展令人失望。在某种程度上，这种困难被认为是复杂遗传以及大量遗传和表型异质性的结果。这个协作应用程序联合了一组专门研究抽动秽语症（TD）的临床专家和统计和分子遗传学家，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，这种资源现在在许多神经精神疾病中很常见；2)为了取得成功，遗传学研究必须关注DNA序列和结构变异的贡献，以及大样本群体中罕见和常见等位基因的贡献；3)对TD遗传病因的进一步了解将最终转化为新的和更有效的方法来治疗这种经常使人衰弱的疾病，从而将显著地造福公众健康。考虑到这些问题，该申请阐述了三个具体目标：具体目标1支持7个美国和2个国际临床站点的持续合作，将在5年内招募4450名TD患者。该队列将包括2995个亲子三人组的子集，允许评估从头DNA序列和结构变异。这个样本将迅速提供给广泛的科学界。Specific Aim 2将支持在该队列中同时进行拷贝数变异（CNV）和全基因组关联研究（GWAS）。此外，研究人员还提出了下一代深度重测序工作，以确认在初步研究中确定的两个高优先级生物学途径的相关性，并对本文提出的CNV、SNP和基因表达研究中最有希望的转录本进行后续研究。最后，Specific Aim 3扩展了nih资助的探索性项目，分析TD受试者的转录组，并将收集、冷冻和储存所有受试者的PAXgene管，以便将来进行基因表达研究，并成为NIMH中心公共资源的一部分。此外，将对300名具有“高优先级”CNVs的受影响受试者进行基因表达分析，研究结构变异对顺式、反式和全基因组表达的影响。

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.