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Cell Rep DOI:10.1016/j.celrep.2018.08.082

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

Publication TypeJournal Article
Year of Publication2018
AuthorsWang, 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, A Willsey, J, State, MW
Corporate AuthorsTourette International Collaborative Genetics Study (TIC Genetics), Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE), Tourette Association of America International Consortium for Genetics (TAAICG)
JournalCell Rep
Volume24
Issue13
Pages3441-3454.e12
Date Published2018 Sep 25
ISSN2211-1247
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.

DOI10.1016/j.celrep.2018.08.082
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30257206?dopt=Abstract

Alternate JournalCell Rep
PubMed ID30257206
PubMed Central IDPMC6475626
Grant ListR01 MH092292 / MH / NIMH NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
R01 MH092516 / MH / NIMH NIH HHS / United States
R01 MH092513 / MH / NIMH NIH HHS / United States
R01 MH092291 / MH / NIMH NIH HHS / United States
K08 MH099424 / MH / NIMH NIH HHS / United States
R01 MH092520 / MH / NIMH NIH HHS / United States
R01 MH092289 / MH / NIMH NIH HHS / United States
R01 MH092290 / MH / NIMH NIH HHS / United States
U01 GM115486 / GM / NIGMS NIH HHS / United States
U24 MH068457 / MH / NIMH NIH HHS / United States
R01 MH092293 / MH / NIMH NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States