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

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.

SUBMITTER: Wang S 

PROVIDER: S-EPMC6475626 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Wang Sheng S   Mandell Jeffrey D JD   Kumar Yogesh Y   Sun Nawei N   Morris Montana T MT   Arbelaez Juan J   Nasello Cara C   Dong Shan S   Duhn Clif C   Zhao Xin X   Yang Zhiyu Z   Padmanabhuni Shanmukha S SS   Yu Dongmei D   King Robert A RA   Dietrich Andrea A   Khalifa Najah N   Dahl Niklas N   Huang Alden Y AY   Neale Benjamin M BM   Coppola Giovanni G   Mathews Carol A CA   Scharf Jeremiah M JM   Fernandez Thomas V TV   Buxbaum Joseph D JD   De Rubeis Silvia S   Grice Dorothy E DE   Xing Jinchuan J   Heiman Gary A GA   Tischfield Jay A JA   Paschou Peristera P   Willsey A Jeremy AJ   State Matthew W MW  

Cell reports 20180901 13

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 enriche  ...[more]

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