Acceleration of risk gene discovery for Tic Disorders through large-scale collaboration

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PROJECT SUMMARY Tourette Syndrome (TS) is a complex neuropsychiatric condition that is characterized by persistent uncontrolled motor and verbal tics. If a patient only has physical or verbal tics but not both, they instead receive a diagnosis of Chronic Tic Disorder (CTD). Both can severely inhibit a patients’ quality of life and livelihood. There is long- standing epidemiological evidence for TS and CTD being heritable conditions that cluster within families. Contemporary genetic studies largely focused on common variation have produced results that are consistent with this, but have not provided a great deal of insight regarding the biology underlying these conditions. Studies of rare coding variation using whole exome sequencing (WES) enable the detection of individual risk genes that when perturbed can substantially increase risk. Currently, there are just three modestly-sized TS/CTD WES studies published, but all strongly support the contribution of rare coding variants to this condition. Unfortunately, however, the total sample size after aggregating these three studies lags well behind other neuropsychiatric conditions such as autism spectrum disorder and schizophrenia. This is despite the fact that TS/CTD are common, disabling and highly heritable conditions. In this proposal, we describe a cost-efficient strategy to markedly increase samples size for TS/CTD WES analyses by capitalizing on existing DNA samples from well- characterized TS/CTD cases and existing WES datasets from TS/CTD cases and controls that have yet to be included in TS/CTD studies. Specifically, we propose a highly feasible two-year study that would ultimately triple the total TS/CTD case WES sample size and accelerate risk gene discovery. We will first generate new WES data for 140 TS/CTD trios and 160 singleton cases from Sweden, all of whom are deeply phenotyped. These data will then be combined with as-yet unpublished WES data from 1474 TS/CTD cases and 15,200 controls. Next, we will integrate our dataset with all WES data from the three published studies mentioned above in order to generate the largest possible sample (1042 trios, 1634 cases and 15,200 controls). This will maximize power for a meta-analysis geared toward high-confidence risk gene discovery. Our comprehensive rare variant analyses will also incorporate measures of common polygenic risk for TS/CTD as well as rich clinical data. This will allow us to begin to examine whether rare and common variation interact to influence meaningful clinical outcomes such as response to behavioral treatment. Finally, we will create a centralized online resource to facilitate the sharing of source code, quality control metrics and gene-based summary statistics for all worldwide TS/CTD WES data. Our goal is to facilitate the work of other TS/CTD researchers to accelerate gene discovery for this understudied condition.