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., Fernandez TV., Buxbaum JD., De Rubeis S., Grice DE., Xing J., Heiman GA., Tischfield JA., Paschou P., Jeremy Willsey A., State MW., Abdulkadir M., Bodmer B., Bromberg Y., Brown LW., Cheon KA., Coffey BJ., Deng L., Elzerman L., Fremer C., Garcia-Delgar B., Gilbert DL., Hagstrøm J., Hedderly T., Heyman I., Hoekstra PJ., Hong HJ., Huyser C., Kim EJ., Kim YK., Kim YS., Koh YJ., Kook S., Kuperman S., Leventhal BL., Ludolph AG., Madruga-Garrido M., Maras A., Mir P., Morer A., Müller-Vahl K., Münchau A., Murphy TL., Plessen KJ., Poisner H., Roessner V., Sanders SJ., Shin EY., Song DH., Song J., Thackray JK., Tübing J., Visscher F., Wanderer S., Woods M., Zhang Y., Zinner SH., Androutsos C., Barta C., Farkas L., Fichna J., Georgitsi M., Janik P., Karagiannidis I., Koumoula A., Nagy P., Puchala J., Rizzo R., Szejko N., Szymanska U., Tarnok Z., Tsironi V., Wolanczyk T., Zekanowski C., Barr CL., Batterson JR., Berlin C., Bruun RD., Budman CL.
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. Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis.
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Michelle Fernandes
Clinical Lecturer & MRC Clinical Research Training Fellow
