Authors

Sheng Wang, China Agricultural University
Jeffrey D. Mandell, University of California, San Francisco
Yogesh Kumar, Purdue University
Nawei Sun, University of California, San Francisco
Montana T. Morris, University of California, San Francisco
Juan Arbelaez, University of California, San Francisco
Cara Nasello, The State University of New Jersey
Shan Dong, University of California, San Francisco
Clif Duhn, University of California, San Francisco
Xin Zhao, University of California, San Francisco
Zhiyu Yang, Purdue University
Shanmukha S. Padmanabhuni, Purdue University
Dongmei Yu, Harvard Medical School
Robert A. King, Yale University
Andrea Dietrich, University of Groningen
Najah Khalifa, Uppsala University
Niklas Dahl, Uppsala University
Alden Y. Huang, University of California, Los Angeles
Benjamin M. Neale, Harvard Medical School
Giovanni Coppola, University of California, Los Angeles
Carol A. Mathews, University of Florida
Jeremiah M. Scharf, Harvard Medical School
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)
Thomas V. Fernandez, Yale University
Joseph D. Buxbaum, Icahn School of Medicine at Mount Sinai
Silvia De Rubeus, Icahn School of Medicine at Mount Sinai
Dorothy E. Grice, Icahn School of Medicine at Mount Sinai
Jinchuan Xing, The State University of New Jersey
Gary A. Heiman, The State University of New Jersey
Jay A. Tischfield, The State University of New Jersey
Peristera Paschou, Purdue UniversityFollow
A Jeremy Wilsey, University of California, San FranciscoFollow
Matthew W. State, University of California, San FranciscoFollow

Abstract

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.

Comments

This is the publishers version of 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. De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis. Cell Rep. 2018 Sep 25;24(13):3441-3454.e12. doi: 10.1016/j.celrep.2018.08.082. Erratum in: Cell Rep. 2018 Dec 18;25(12):3544. PMID: 30257206; PMCID: PMC6475626.

Keywords

10.1016/j.celrep.2018.08.082

Date of this Version

9-25-2018

DOI

10.1016/j.celrep.2018.08.082

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