Refining the Tourette Syndrome phenotype across diagnoses to aid gene discovery

描述（由申请人提供）：这项拟议的研究利用了Tourette综合征（TS）个体和家族的大型临床和遗传数据集，以确定可遗传的基于基因组的表型，并进行定量全基因组关联研究（qGWAS），最终目标是确定导致TS易感性的遗传变异。TS是一种复杂的发育性神经精神障碍，在全球范围内影响1/150至1/300的儿童。虽然TS的核心特征（存在运动和发声抽搐）相当简单，但TS在表型上是多样的，一些个体仅表现出轻度抽搐，几乎没有功能影响，而另一些个体表现出中度至重度抽搐，具有明显的功能障碍。所有年龄组的所有抽动严重程度的个体也可能经历一系列导致显著功能障碍的并发症，最常见的是强迫症（OCD）和注意缺陷多动障碍（ADHD），但也包括其他情绪，焦虑和破坏性行为障碍。这种表型异质性使TS的病因学和治疗研究变得复杂，并影响临床护理。本研究将使用新的分析方法，如因子混合模型，以1）检查共发精神疾病的频率，模式和相关性，2）根据抽搐和相关症状的模式和共发条件识别TS表型亚型（包括自闭症谱系症状），3）检查这些亚表型的遗传性和传播模式，和4）用最可遗传的鉴定的亚表型进行定量的全基因组关联研究。我们拥有2,100多名TS患者及其2,500名生物学一级亲属的广泛临床数据（终身和目前的临床学），以及1006例TS病例的全基因组遗传数据，为我们进一步了解TS提供了无与伦比的机会。本申请中提出的工作在临床上和科学上都具有相关性，临床上，因为我们将能够确定共同发生的疾病的比率和模式，如所提到的，共同发生的疾病是TS中大部分损伤的原因，科学上，因为它提供了额外的治疗方案。 为TS和其他相关神经发育障碍的病因学和病理生理学的遗传学和其他研究提供了途径。

DESCRIPTION (provided by applicant): This proposed research leverages a large clinical and genetic dataset of individuals and families with Tourette Syndrome (TS) to identify heritable symptom-based phenotypes and conduct quantitative genome-wide association studies (qGWAS) with the ultimate goal of identifying genetic variants that contribute to TS susceptibility. TS is a complex developmental neuropsychiatric disorder that affects 1/150 to 1/300 children world-wide. Although the core features of TS (the presence of motor and vocal tics) are fairly straightforward, TS is phenotypically diverse, with some individuals manifesting only mild tics with little to no functional impact and others manifesting moderate to severe tics with marked impairment. Individuals at all levels of tic severity and in all age groups may also experience a range of co-occurring conditions that lead to significant functional impairment, most commonly obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), but also including other mood, anxiety, and disruptive behavior disorders. This phenotypic heterogeneity has complicated etiological and treatment studies of TS, as well as impacting clinical care. This study will use novel analytic approaches such as factor mixture modeling to 1) examine the frequencies, patterns, and correlates of co-occurring psychiatric disorders, 2) identify TS phenotypic subtypes based on patterns of tic and related symptoms and co-occurring conditions (including autism spectrum symptoms), 3) examine the heritabilites and transmission patterns of these subphenotypes, and 4) conduct quantitative genome-wide association studies with the most heritable of the identified subphenotypes. We have extensive clinical data (lifetime and current symptomatology) on over 2,100 TS-affected individuals and 2,500 of their biological first-degree relatives, as well as genome-wide genetic data on 1006 of the TS cases, providing an unparalleled opportunity to further our understanding of the presentation TS. The work proposed in this application has relevance both clinically, as we will be able to determine rates and patterns of co-occurring disorders, which, as mentioned, are responsible for the majority of the impairment in TS, and scientifically, as it provides additional avenues for genetic and other investigations into the etiology and pathophysiology of TS and other related neurodevelopmental disorders.