6/8-Collaborative genomic studies of Tourette Disorder

摘要/摘要：抽动秽语症（Tourette Disorder， TD）是一种发展性神经精神综合征，以持续的声音和运动抽搐为特征。虽然最初被认为是罕见的，但目前全球患病率估计为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基因的重要作用，但在识别风险等位基因方面进展缓慢。这种困难被认为部分是复杂遗传和大量遗传和表型异质性的结果。这项合作研究联合了一个国际小组，由专门研究TD的高度专家临床医生与统计和分子遗传学家组成，并受到三个中心假设的推动：1)TD基因发现的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)基于大量其他遗传复杂疾病的最新数据，TD的全面基因组学研究将需要大样本量，并应关注罕见和常见等位基因以及序列和结构变异的潜在贡献；3)对TD遗传病因的进一步了解将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，因此将具有显著的公共卫生效益。该申请详细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），并在一年内公开收集DNA，细胞系，cDNA/RNA和表型数据。样本将包括3195个欧洲高加索（EC）先证者的子集；1250个韩国先证者，以及3295个允许研究新生变异的亲子三人组。我们还将每年招募至少10个有4个或更多受影响成员的TD谱系，作为基于家族的基因发现的资源。具体目标2：采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 HumanOmni2.5 -Quad BeadChips上对样品进行基因分型，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）；全外显子组测序将用于选择，多重影响的TD谱系（Aim 2C）；我们将在两个时间点使用下一代重测序策略（Aim 2D）对上述研究中发现的最有希望的基因座进行随访，评估3195名EC和3195名匹配对照中至少50个基因；具体目标3：对TD受试者的300个转录组进行初步分析，以研究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。该项目将免费收集所有受试者的PAXgene试管，并将其提供给科学界，以便我们小组和其他人将来进行研究。

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. PUBLIC HEALTH RELEVANCE: Project Narrative: Tourette Disorder (TD) is a poorly understood, often debilitating neuropsychiatric disorder characterized by a combination of persistent vocal and motor tics, affecting between 3 in 1000 and 1 in 100 people worldwide, predominantly children. Our international team of experts in TD and other mental disorders proposes to recruit 5050 affected individuals, undertake a comprehensive gene discovery effort, and make the collected biomaterials and clinical data rapidly available to the broad scientific community, thereby enabling both current and future TD research. Understanding the causes of TD may facilitate the development of novel and improved treatments.