1/8-Collaborative genomic studies of Tourette Disorder

描述(申请人提供)：摘要/摘要：多发性抽动症(TD)是一种以持续性发声和运动抽搐相结合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进展缓慢。这一困难被认为部分是复杂的遗传和大量的遗传和表型异质性的结果。这项合作研究将一个专门研究TD的国际高度专家临床医生小组与统计和分子遗传学家联合起来，并基于三个中心假设：1)TD基因发现的一个关键限制因素是公共可用的大规模生物材料资源的缺乏，这种资源现在对许多神经精神疾病来说是司空见惯的；2)基于来自许多其他遗传复杂疾病的最新数据，对TD进行全面的基因组学研究将需要大量样本，并应关注稀有和常见等位基因以及序列和结构变异的潜在贡献；3)对TD的遗传病因的更多了解将转化为治疗这种经常使人虚弱的疾病的新的和更有效的方法，因此将对公众健康产生显著的好处。该申请阐述了三个具体目标：具体目标1：招募5050名TD患者(及其家庭成员)，并在收集一年内公开DNA、细胞系、cDNA/RNA和表型数据。样本将包括3195名欧洲高加索(EC)先证者、1250名韩国先证者和3295名亲子三人的子集，以研究从头开始的变异。我们还将每年招募至少10个有4个或以上受影响成员的TD家系，作为以家庭为基础的基因发现的资源。具体目标2：使用最先进的技术来识别和确认导致TD的罕见和常见变异。我们将在Illumina Human Omni2.5-Quad BeadChips上对样本进行基因分型，以支持拷贝数变异(CNV)分析(Aim 2A)和全基因组关联研究(Gwas)(Aim 2B)；整个外显子组测序将用于选择、多个受影响的TD家系(Aim 2C)；我们将在两个时间点使用汇集的下一代重新测序策略(Aim 2D)跟踪上述研究中确定的最有希望的基因座，评估总共3195个EC和3195个匹配对照中的至少50个基因；具体目标3：对300个TD受试者的转录本进行初步分析，以调查选定的结构和序列变异对顺式、反式和全基因组表达的影响。这个项目不需要任何费用，PAX基因试管将从所有受试者中收集，并提供给科学界，以便我们团队和其他人进行未来的研究。

DESCRIPTION (provided by applicant): SUMMARY/ABSTRACT: 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%. 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 in identifying risk alleles has been slow. This difficulty is thought to be, in part, a consequence of complex inheritance and substantial genetic and phenotypic heterogeneity. This collaborative study unites an international group of highly expert clinicians specializing in TD with statistical and molecular geneticists and is motivated by three central hypotheses: 1) that a key rate- limiting factor for TD gene discovery has been the paucity of publically available, large-scale biomaterial resources of the kind that are now commonplace for many neuropsychiatric disorders; 2) based on recent data from a host of other genetically complex disorders, a comprehensive genomics study of TD will require large samples sizes and should focus on the potential contribution of rare as well as common alleles and both sequence and structural variants; and 3) an increased understanding of the genetic etiology of TD will translate into novel and more effective approaches to treating this often-debilitating disorder, and consequently will have marked public health benefits. The application elaborates three specific aims: Specific Aim 1: To recruit 5050 individuals with TD (and their family members), and make DNA, cell-lines, cDNA/RNA and phenotypic data publicly available within one year of collection. The sample will include a subset of 3195 European Caucasian (EC) probands; 1250 Korean probands, and 3295 parent-child trios allowing for the study of de novo variation. We will also recruit each year at least 10 TD pedigrees with 4 or more affected members as a resource for family-based gene discovery. Specific Aim 2: To employ state-of-the-art techniques to identify and confirm rare and common variants contributing to TD. We will genotype the sample on Illumina HumanOmni2.5 -Quad BeadChips to support copy number variation (CNV) analysis (Aim 2A) and genome wide association studies (GWAS) (Aim 2B); whole exome sequencing will be employed in select, multiply-affected TD pedigrees (Aim 2C); and we will follow up on the most promising loci identified in the aforementioned studies using a pooled next generation re-sequencing strategy (Aim 2D) at two time points, evaluating a minimum of 50 genes in a total of 3195 EC and 3195 matched controls; Specific Aim 3: To perform preliminary analyses of 300 transcriptomes of TD subjects to investigate the implications of selected structural and sequence variations for cis, trans and genome-wide expression. With no cost to this project, PAXgene tubes will be collected from all subjects and made available to the scientific community to enable future studies by our group and others.