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De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

2018; Cell Press; Volume: 24; Issue: 13 Linguagem: Inglês

10.1016/j.celrep.2018.08.082

2639-1856

Sheng Wang, Jeffrey D. Mandell, Yogesh Kumar, Nawei Sun, Montana T. Morris, Juan David Arbelaez, Cara Nasello, Shan Dong, Clif Duhn, Xin Zhao, Zhiyu Yang, Shanmukha Sampath Padmanabhuni, Dongmei Yu, Robert A. King, Andrea Dietrich, Najah Khalifa, Niklas Dahl, Alden Y. Huang, Benjamin M. Neale, Giovanni Coppola, Carol A. Mathews, Jeremiah M. Scharf, Thomas Fernandez, Joseph D. Buxbaum, Silvia De Rubeis, Dorothy E. Grice, Jinchuan Xing, Gary A. Heiman, Jay A. Tischfield, Peristera Paschou, A. Jeremy Willsey, Matthew W. State, Mohamed Abdulkadir, Juan David Arbelaez, Benjamin Bodmer, Yana Bromberg, Lawrence W. Brown, Keun‐Ah Cheon, Barbara J. Coffey, Li Deng, Andrea Dietrich, Dong Shan, Clif Duhn, Lonneke Elzerman, Thomas V. Fernandez, Carolin Fremer, Blanca García-Delgar, Donald L. Gilbert, Dorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Gary A. Heiman, Isobel Heyman, Pieter J. Hoekstra, Hyun Ju Hong, Chaim Huyser, Eunjoo Kim, Young Key Kim, Young-Shin Kim, Robert A. King, Yun‐Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett Leventhal, Andrea G. Ludolph, Marcos Madruga-Garrido, Jeffrey D. Mandell, Athanasios Maras, Pablo Mir, Àstrid Morer, Montana T. Morris, Kirsten Müller‐Vahl, Alexander Münchau, Tara Murphy, Cara Nasello, Kerstin Jessica Plessen, Hannah Poisner, Veit Roessner, Stephan Sanders, Eun-Young Shin, Dong‐Ho Song, Jungeun Song, Matthew W. State, Nawei Sun, Joshua K. Thackray, Jay A. Tischfield, Jennifer Tübing, Frank Visscher, Sina Wanderer, Sheng Wang, A. Jeremy Willsey, Martin Woods, Jinchuan Xing, Yeting Zhang, Xin Zhao, Samuel H. Zinner, Christos Androutsos, Csaba Barta, Luca Farkas, Jakub Fichna, Marianthi Georgitsi, Piotr Janik, Iordanis Karagiannidis, Anastasia Koumoula, Peter Nagy, Peristera Paschou, Joanna Puchala, Renata Rizzo, Natalia Szejko, Urszula Szymańska, Zsanett Tárnok, Vaia Tsironi, Tomasz Wolañczyk, Cezary Żekanowski, Cathy L. Barr, James R. Batterson, Cheston M. Berlin, Ruth D. Bruun, Cathy L. Budman, Daniëlle C. Cath, Sylvain Chouinard, Giovanni Coppola, Nancy J. Cox, Sabrina M. Darrow, Lea K. Davis, Yves Dion, Nelson B. Freimer, Marco A. Grados, Matthew E. Hirschtritt, Alden Y. Huang, Cornelia Illmann, Robert A. King, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, Carol A. Mathews, William M. MacMahon, Benjamin M. Neale, Michael S. Okun, Lisa Osiecki, David L. Pauls, Daniëlle Posthuma, Vasily Ramensky, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Jeremiah M. Scharf, Harvey S. Singer, Jan Smit, Jae-Hoon Sul, Dongmei Yu,

Plant Reproductive Biology

Highlights•Recurrent de novo variants identify a new high-confidence TD risk gene: CELSR3•Genes involved in cell polarity are more likely to be disrupted by de novo variants•De novo sequence variants may carry more risk in simplex families, female probands•De novo CNVs occur 2 to 3 times more often in TD probands than in matched controlsSummaryWe 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.Graphical abstract