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

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)

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)3441-3454.e12
JournalCell Reports
Volume24
Issue number13
DOIs
StatePublished - Sep 25 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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