De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
Wang S., Mandell JD., Kumar Y., Sun N., Morris MT., Arbelaez J., Nasello C., Dong S., Duhn C., Zhao X., Yang Z., Padmanabhuni SS., Yu D., King RA., Dietrich A., Khalifa N., Dahl N., Huang AY., Neale BM., Coppola G., Mathews CA., Scharf JM., Tourette International Collaborative Genetics Study (TIC Genetics) ., Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE) ., Tourette Association of America International Consortium for Genetics (TAAICG) ., Fernandez TV., Buxbaum JD., De Rubeis S., Grice DE., Xing J., Heiman GA., Tischfield JA., Paschou P., Willsey AJ., State MW.
We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.