Large-scale collaborative genetic and epigenetic studies of Tourette Syndrome

项目总结/摘要 抽动秽语综合征（TS）影响全球约1%的儿童，在儿童中的发病率是儿童的三倍。 男孩比女孩。TS是一种高度遗传的非孟德尔神经精神疾病 紊乱虽然抽搐是TS的定义特征，但>85%的患者有额外的抽搐。 神经精神障碍，最明显的是强迫症（OCD）和注意力缺陷 多动症（ADHD），这被认为是病因相关，并有助于 TS患者中常见的污名化和功能障碍。异常 皮质-纹状体-丘脑-皮质（CSTC）回路的发展和/或维持被认为 是TS及其合并症的病理生理学基础;然而， 这种疾病的基础，以及TS，OCD和ADHD之间的遗传关系，在很大程度上仍然存在 难以捉摸。尽管存在这些挑战，TS遗传学领域正处于加速基因转移的边缘。 多个美国和欧洲财团进行全基因组关联研究 在大型患者队列中进行TS的GWAS（GWAS）和拷贝数变异（CNV）分析。团队 领导这项申请的调查人员代表了所有主要的TS联盟， 大约12，000例TS病例和50，000例祖先匹配的对照。我们将采用创新 进行大规模GWAS和CNV Meta和大型分析的方法，目标是 识别导致TS易感性的个体风险变异，以及阐明 疾病及其合并症的潜在遗传结构。然后，我们将整合 结果基因组数据与功能表观基因组学，转录组学和神经成像数据， 确定特定的大脑区域，细胞类型和神经发育时间点，其中TS 易感基因功能障碍导致疾病。我们还将研究生物性别的作用 TS的基因基础这一综合努力将利用跨越各个领域的数据 包括神经基因组学和神经表观基因组学，神经发育生物学， 和神经成像我们的研究将确定组织，细胞类型和电路， TS遗传风险最集中，也是最相关的发育期。 这种在分子、细胞和电路水平上的TS发病机制的时空定位将 提供关键信息，指导建立未来的TS疾病模型， 可能为新的治疗方法指明目标。

PROJECT SUMMARY/ABSTRACT Tourette Syndrome (TS) affects ~1% of children worldwide, and is three times more common in boys than in girls. TS is one of the most highly heritable non-Mendelian neuropsychiatric disorders. Although tics are the defining feature of TS, >85% of patients have additional neuropsychiatric disorders, most notably obsessive-compulsive (OCD) and attention-deficit hyperactivity disorder (ADHD), which are thought to be etiologically related, and which contribute to the stigmatization and functional impairment commonly seen in TS patients. Abnormal development and/or maintenance of cortico-striato-thalamo-cortical (CSTC) circuits is thought to underlie the pathophysiology of TS and its comorbidities; however, the molecular and cellular basis of the disorder, and the genetic relationships between TS, OCD, and ADHD, remain largely elusive. Despite these challenges, the field of TS genetics is on the verge of accelerated gene discovery, with multiple US and European consortia conducting genome-wide association studies (GWAS) and copy number variant (CNV) analyses for TS in large patient cohorts. The team of investigators leading this application represent all of the major TS consortia, and bring together approximately 12,000 TS cases and 50,000 ancestry-matched controls. We will apply innovative approaches to conduct large-scale GWAS and CNV meta and mega-analyses, with the goal of identifying individual risk variants that lead to TS susceptibility, as well as elucidating the underlying genetic architecture of the disorder and its comorbidities. We will then integrate the resulting genomic data with functional epigenomic, transcriptomic, and neuro-imaging data to determine the specific brain regions, cell types and neurodevelopmental time points where TS susceptibility gene dysfunction leads to disease. We will also examine the role of biological sex in the genetic underpinnings of TS. This integrative effort will utilize data spanning various fields of neuroscience including neuro-genomics and neuro-epigenomics, neurodevelopmental biology, and neuro-imaging. Our study will identify the tissues, cell types and circuits where aggregated TS genetic risk is most highly concentrated, as well as the most relevant developmental period(s). This spatio-temporal localization of TS pathogenesis at the molecular, cellular and circuit level will provide critical information to guide the establishment of future disease models of TS and potentially point to targets for new treatments.