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多发性抽动症(TS)患者和家庭的大量临床和遗传数据集来确定基于症状的可遗传表型，并进行量化的全基因组关联研究(QGWAS)，最终目标是识别导致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，全世界有1/150至1/300的儿童受到影响。虽然TS的核心特征(运动和发声抽搐的存在)相当简单，但TS的表型是多样化的，一些人只表现出轻微的抽搐，几乎没有功能影响，而另一些人表现出中到重度的抽搐并有明显的损害。所有严重程度的抽搐和所有年龄段的人也可能经历一系列共同发生的疾病，导致严重的功能障碍，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。这种表型的异质性使TS的病因和治疗研究变得复杂，也影响了临床治疗。这项研究将使用新的分析方法，如因子混合模型，1)检查共发精神疾病的频率、模式和相关性，2)根据抽动和相关症状的模式和共生条件(包括自闭症谱系症状)确定TS表型，3)检查这些亚型的遗传性和传播模式，4)与已识别的最可遗传的亚型进行全基因组定量关联研究。我们拥有超过2,100名TS患者及其2,500名生物一级亲属的广泛临床数据(一生和当前症状)，以及1006例TS患者的全基因组遗传数据，这为我们进一步了解TS提供了一个无与伦比的机会。本申请中提出的工作既具有临床意义，因为我们将能够确定共生障碍的比率和模式，如上所述，这是导致TS损害的主要原因，并且具有科学意义，因为它提供了额外的 对TS和其他相关神经发育障碍的病因和病理生理学进行遗传学和其他研究的途径。

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.