Tourette Syndrome (TS) affects ~1% of children worldwide, and is three times more common in boys than in girls. TS is one of the most highly heritable non-Mendelian neuropsychiatric disorders. Although tics are the defining feature of TS, >85% of patients have additional neuropsychiatric disorders, most notably obsessive-compulsive (OCD) and attention-deficit hyperactivity disorder (ADHD), which are thought to be etiologically related, and which contribute to the stigmatization and functional impairment commonly seen in TS patients. Abnormal development and/or maintenance of cortico-striato-thalamo-cortical (CSTC) circuits is thought to underlie the pathophysiology of TS and its comorbidities; however, the molecular and cellular basis of the disorder, and the genetic relationships between TS, OCD, and ADHD, remain largely elusive. Despite these challenges, the field of TS genetics is on the verge of accelerated gene discovery, with multiple US and European consortia conducting genome-wide association studies (GWAS) and copy number variant (CNV) analyses for TS in large patient cohorts. The team of investigators leading this application represent all of the major TS consortia, and bring together approximately 12,000 TS cases and 50,000 ancestry-matched controls. We will apply innovative approaches to conduct large-scale GWAS and CNV meta and mega-analyses, with the goal of identifying individual risk variants that lead to TS susceptibility, as well as elucidating the underlying genetic architecture of the disorder and its comorbidities. We will then integrate the resulting genomic data with functional epigenomic, transcriptomic, and neuro-imaging data to determine the specific brain regions, cell types and neurodevelopmental time points where TS susceptibility gene dysfunction leads to disease. We will also examine the role of biological sex in the genetic underpinnings of TS. This integrative effort will utilize data spanning various fields of neuroscience including neuro-genomics and neuro-epigenomics, neurodevelopmental biology, and neuro-imaging. Our study will identify the tissues, cell types and circuits where aggregated TS genetic risk is most highly concentrated, as well as the most relevant developmental period(s). This spatio-temporal localization of TS pathogenesis at the molecular, cellular and circuit level will provide critical information to guide the establishment of future disease models of TS and potentially point to targets for new treatments.
Tourette Syndrome (TS) is a common, highly heritable neuropsychiatric disorder, though few definitive TS susceptibility genes have been identified due to the absence of large-scale, well-characterized datasets. This research represents a collaboration of all major TS genetic research consortia that will bring together approximately 12,000 individuals with TS and 50,000 ancestry-matched controls for genome-wide analyses to identify definitive TS risk genes. We will then integrate these results with a wide range of emerging information about gene regulation and expression in specific cells and tissues in the brain across human development, as well as brain imaging information, that together can help to identify when and where in the brain the TS risk genes work together to cause disease, define the tissues and/or cell types in which to conduct future studies of disease mechanisms, and potentially point to targets for new treatments.
