Integrating Common and Rare Variation to Discover Genes Associated with Tourette Syndrome Tourette Syndrome (TS) is a childhood-onset, neuropsychiatric disorder that is highly heritable, though discovery of definitive TS susceptibility genes has been challenging. This multi-PD/PI application, which aims to identify new susceptibility genes for TS and to examine their relationship to clinical disease outcomes, continues the work of the Tourette Association of America International Consortium for Genetics (TAAICG), the longest standing research collaborative group dedicated to understanding the genetic causes underlying TS. The research plan consists of: 1) Whole exome sequencing of 1,400 TS parent-proband trios to identify rare, potentially deleterious genetic variants of relevance to TS; 2) Genome-wide analyses of de novo copy-number variation (CNVs) in these 1,400 TS trios to identify high impact, rare structural variation associated with TS; 3) Use of information about TS-relevant common variation from existing genome-wide association study (GWAS) data on 4,819 TS cases and 9,488 controls to prioritize a subset of 800 of the 1,400 TS trios for cryptic structural variation sequencing studies to capture de novo gene-disrupting chromosomal rearrangements not detectable by standard techniques; and 4) Integration of identified rare and common variation to develop prediction models of disease outcome, including tic severity, functional impairment, tic persistence into adulthood, and psychiatric comorbidity. The proposed study will be conducted at Massachusetts General Hospital, University of Florida, University of California at Los Angeles, and Vanderbilt University Medical Center, each who have complementary expertise in computational biology, analysis of next-generation sequencing data, and integration of disease-associated DNA variation with clinical data. This proposal provides a unique and exciting opportunity to rapidly advance the goal of identifying the biological basis of this complex and important model neuropsychiatric disorder which in the future could lead to prediction of disease severity and to targeted treatments and/or prevention.