Tourette Syndrome (TS) is characterized by multiple, persistent motor and vocal tics and affects approximately 1% of children worldwide. There is no cure for TS and efforts to develop novel treatments are hampered by our limited understanding of the underlying neurobiology and brain structural and functional deficits. Although tics represent the hallmark feature of TS, up to 90% of patients present with additional neuropsychiatric disorders, including Obsessive Compulsive Disorder (OCD up to 50% of TS patients), Attention Deficit Hyperactivity Disorder (ADHD up to 54.3%), Autism Spectrum Disorders (ASD up to 20%), Major Depressive Disorder (MDD up to 26%), and Anxiety Disorders (AXD up to 36%). These comorbidities contribute to decreased quality of life and introduce etiological and phenotypic heterogeneity that further hampers efforts to elucidate the TS neurobiology. Here, we are proposing to investigate TS-related brain structure and function at a large scale but also to identify those factors that lead to high comorbidity with other disorders. Motivated by international collaborative studies on the genetics and neuroimaging of TS led by the PI, we bring together all major worldwide collaborative efforts on neuroimaging and genetics for TS and aim to integrate with equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. We take advantage of access to data, resources and standardized pipelines from the ENIGMA (Enhancing Neuroimaging Genetics through Meta- Analysis) consortium and the Psychiatric Genomics Consortium (PGC). First, we will establish the ENIGMA-TS working group, for which PI Paschou has already laid the groundwork, with 17 sites from nine countries having agreed to contribute existing neuroimaging and clinical data from 1,930 cases and controls. We will pool together T1 structural imaging data as well as rsfMRI and DTI data. Second, we will pursue the largest neuroimaging studies for TS to date aiming to understand the pathophysiology of the disorder. Pursuing cross-disorder analysis, we will also integrate our TS neuroimaging data with existing ENIGMA data for the most frequently comorbid disorders in TS (OCD, ADHD, ASD, MDD, and AXD). Third, we will aim to uncover brain regions that correlate to genetic background in TS and related disorders. To do this we will analyze TS genomewide association studies (GWAS) but also pursue cross-disorder GWAS for TS and comorbid disorders. We will leverage our findings from the first large-scale cross-disorder GWAS meta-analysis for TS, OCD, ADHD, ASD (led by the PI), as well as access to data from ENIGMA GWAS on brain structure from more than 50,000 individuals and the UK Biobank on additional 10,000 individuals. Importantly, we will also leverage access to population-based cohorts (ABCD and Generation R), with longitudinal brain imaging, clinical but also genetic information in order to replicate our findings to diverse populations and explore correlat...