Large-scale collaborative genetic and epigenetic studies of Tourette Syndrome

项目摘要/摘要 抽动秽语综合征(TS)影响全球约1%的儿童，在 男孩比女孩多。TS是遗传性最强的非孟德尔神经精神病学之一 精神错乱。尽管抽搐是TS的定义特征，但85%的患者有额外的 神经精神障碍，尤其是强迫症(OCD)和注意力缺陷 多动障碍(ADHD)，被认为与病因有关，并对 与TS患者常见的污名化和功能障碍有关。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及其共病的病理生理学基础；然而，分子和细胞 这种疾病的基础以及TS、强迫症和ADHD之间的遗传关系在很大程度上仍然存在 难以捉摸。尽管有这些挑战，TS遗传学领域仍处于加速基因的边缘 发现，多个美国和欧洲财团进行全基因组关联研究 (GWAS)和拷贝数变异(CNV)分析在大型患者队列中的TS。这支队伍 领导这一申请的调查人员代表所有主要的TS财团，并将 大约12,000名TS患者和50,000名祖先匹配的对照组。我们将应用创新 进行大规模GWAS和CNV元分析和巨型分析的方法，目标是 确定导致TS易感性的个体风险变量，并阐明 这种疾病及其共病的潜在遗传结构。然后，我们将集成 产生的基因组数据与功能性表观基因组、转录和神经成像数据一起 确定TS的特定脑区、细胞类型和神经发育时间点 易感基因功能障碍导致疾病。我们还将研究生物性行为的作用。 在TS的基因基础上。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。我们的研究将确定聚集在一起的组织、细胞类型和回路 TS的遗传风险最集中，也是最相关的发育期(S)。 这种在分子、细胞和电路水平上对TS发病机制的时空定位将 提供关键信息以指导建立未来的TS和 可能会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.