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.