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图雷特综合征（TS）个体和家庭的大型临床和遗传数据集来确定可遗传的基于症状的表型，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，影响全球1/150至1/300的儿童。虽然TS的核心特征（运动和声音抽搐的存在）相当简单，但TS的表型多样，一些个体仅表现为轻度抽搐，几乎没有功能影响，而另一些个体表现为中度至重度抽搐，并伴有明显的损伤。所有抽动严重程度和所有年龄组的个体也可能经历一系列导致严重功能损害的共同发生条件，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复杂化，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)检查共同发生的精神疾病的频率、模式和相关性；2)根据抽动症和相关症状以及共同发生的疾病（包括自闭症谱系症状）的模式确定TS表型亚型；3)检查这些亚表型的遗传性和传播模式。4)对鉴定出的亚表型中最具遗传性的进行定量全基因组关联研究。我们拥有2100多名TS患者及其2500名一级亲属的广泛临床数据（终生和当前症状学），以及1006例TS病例的全基因组遗传数据，为进一步了解TS的表现提供了无与伦比的机会。本应用程序中提出的工作具有临床相关性，因为我们将能够确定共同发生的疾病的比率和模式，如前所述，是造成TS损伤的主要原因，科学地说，因为它提供了额外的

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.