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

80 Pages Posted: 8 Jun 2018 Sneak Peek Status: Review Complete

See all articles by Sheng Wang

Sheng Wang

University of California, San Francisco (UCSF) - Department of Psychiatry

Jeffrey D. Mandell​

University of California, San Francisco (UCSF) - Department of Psychiatry

Yogesh Kumar​

Purdue University - Department of Biological Sciences

Nawei Sun​

University of California, San Francisco (UCSF) - Department of Psychiatry

Montana T. Morris

University of California, San Francisco (UCSF) - Department of Psychiatry

Juan Arbelaez

University of California, San Francisco (UCSF) - Department of Psychiatry

Cara Nasello

Rutgers, The State University of New Jersey - Department of Genetics

Shan Dong​

University of California, San Francisco (UCSF) - Department of Psychiatry

Clif Duhn​

University of California, San Francisco (UCSF) - Department of Psychiatry

Xin Zhao

University of California, San Francisco (UCSF) - Department of Psychiatry

Zhiyu Yang

Purdue University - Department of Biological Sciences

Shanmukha S. Padmanabhuni

Purdue University - Department of Biological Sciences

Dongmei Yu

Harvard University - Center for Human Genetic Research

Robert A. King

Yale University - Child Study Center

Andrea Dietrich

University of Groningen - Department of Child and Adolescent Psychiatry

Najah Khalifa

Uppsala University - ​Department of Neuroscience

Niklas Dahl

Uppsala University - Department of Immunology

Alden Y. Huang

University of California, Los Angeles (UCLA) - Department of Neurology

Benjamin M. Neale

Harvard University - Center for Human Genetic Research

Giovanni Coppola

University of California, Los Angeles (UCLA) - Department of Neurology

Carol A. Mathews​

University of Florida - Department of Psychiatry

Jeremiah M. Scharf

Harvard University - Center for Human Genetic Research

Tourette International Collaborative Genetics (TIC Genetics)

Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE)

Tourette Association of America International Consortium for Genetics (TAAICG)

Thomas V. Fernandez

Yale University - Child Study Center

Joseph D. Buxbaum

Icahn School of Medicine at Mount Sinai - Department of Psychiatry; Icahn School of Medicine at Mount Sinai - Department of Genetics and Genomic Sciences; Icahn School of Medicine at Mount Sinai - Icahn Institute for Genomics and Multiscale Biology; Icahn School of Medicine at Mount Sinai - Seaver Autism Center for Research and Treatment; James J. Peters Veterans Affairs Medical Center - Mental Health Care Center

Silvia De Rubeis

Mount Sinai Health System - Department of Psychiatry

Dorothy E. Grice

Mount Sinai Health System - Department of Psychiatry

Jinchuan Xing​

Rutgers, The State University of New Jersey - Department of Genetics

Gary A. Heiman​

Rutgers, The State University of New Jersey - Department of Genetics

Jay A. Tischfield

Rutgers, The State University of New Jersey - Department of Genetics

Peristera Paschou

Purdue University - Department of Biological Sciences

A. Jeremy Willsey

University of California, San Francisco (UCSF) - Department of Psychiatry

Matthew W. State

University of California, San Francisco (UCSF) - Department of Psychiatry

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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 two new high confidence TD risk genes, CELSR3 (Cadherin EGF LAG Seven-Pass G-Type Receptor 3) and OPA1 (Mitochondrial Dynamin-Like GTPase); 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.

Suggested Citation

Wang, Sheng and Mandell​, Jeffrey D. and Kumar​, Yogesh and Sun​, Nawei and Morris, Montana T. and Arbelaez, Juan and Nasello, Cara and Dong​, Shan and Duhn​, Clif and Zhao, Xin and Yang, Zhiyu and Padmanabhuni, Shanmukha S. and Yu, Dongmei and King, Robert A. and Dietrich, Andrea and Khalifa, Najah and Dahl, Niklas and Huang, Alden Y. and Neale, Benjamin M. and Coppola, Giovanni and Mathews​, Carol A. and Scharf, Jeremiah M. and , Tourette International Collaborative Genetics (TIC Genetics) and Initiative (TSGENESEE), Tourette Syndrome Genetics Southern and Eastern Europe and Genetics (TAAICG), Tourette Association of America International Consortium for and Fernandez, Thomas V. and Buxbaum, Joseph D. and De Rubeis, Silvia and Grice, Dorothy E. and Xing​, Jinchuan and Heiman​, Gary A. and Tischfield, Jay A. and Paschou, Peristera and Willsey, A. Jeremy and State, Matthew W., De Novo Sequence and Copy Number Variants are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis (2018). Available at SSRN: https://ssrn.com/abstract=3188485 or http://dx.doi.org/10.2139/ssrn.3188485
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sheng Wang

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Jeffrey D. Mandell​

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Yogesh Kumar​

Purdue University - Department of Biological Sciences

West Lafayette, IN 47907
United States

Nawei Sun​

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Montana T. Morris

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Juan Arbelaez

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Cara Nasello

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Shan Dong​

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Clif Duhn​

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Xin Zhao

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Zhiyu Yang

Purdue University - Department of Biological Sciences

West Lafayette, IN 47907
United States

Shanmukha S. Padmanabhuni

Purdue University - Department of Biological Sciences

West Lafayette, IN 47907
United States

Dongmei Yu

Harvard University - Center for Human Genetic Research

55 Fruit Street Boston
Boston, MA 02114
United States

Robert A. King

Yale University - Child Study Center

New Haven, CT 06520
United States

Andrea Dietrich

University of Groningen - Department of Child and Adolescent Psychiatry

P.O. Box 800
9700 AH Groningen, 9700 AV
Netherlands

Najah Khalifa

Uppsala University - ​Department of Neuroscience

Box 513
Uppsala, 751 20
Sweden

Niklas Dahl

Uppsala University - Department of Immunology

Box 513
Uppsala, 751 20
Sweden

Alden Y. Huang

University of California, Los Angeles (UCLA) - Department of Neurology

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Benjamin M. Neale

Harvard University - Center for Human Genetic Research

55 Fruit Street Boston
Boston, MA 02114
United States

Giovanni Coppola

University of California, Los Angeles (UCLA) - Department of Neurology

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Carol A. Mathews​

University of Florida - Department of Psychiatry

1600 SW Archer Rd
M509
Gainesville, FL 32610
United States

Jeremiah M. Scharf

Harvard University - Center for Human Genetic Research

55 Fruit Street Boston
Boston, MA 02114
United States

Thomas V. Fernandez

Yale University - Child Study Center

New Haven, CT 06520
United States

Joseph D. Buxbaum

Icahn School of Medicine at Mount Sinai - Department of Psychiatry

New York, NY 10025
United States

Icahn School of Medicine at Mount Sinai - Department of Genetics and Genomic Sciences

1425 Madison Avenue
New York, NY 10029
United States

Icahn School of Medicine at Mount Sinai - Icahn Institute for Genomics and Multiscale Biology

1425 Madison Ave
New York, NY 10029
United States

Icahn School of Medicine at Mount Sinai - Seaver Autism Center for Research and Treatment

New York City, NY
United States

James J. Peters Veterans Affairs Medical Center - Mental Health Care Center

Bronx, NY
United States

Silvia De Rubeis

Mount Sinai Health System - Department of Psychiatry

New York, NY 10025
United States

Dorothy E. Grice

Mount Sinai Health System - Department of Psychiatry

New York, NY 10025
United States

Jinchuan Xing​

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Gary A. Heiman​

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Jay A. Tischfield

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Peristera Paschou

Purdue University - Department of Biological Sciences ( email )

West Lafayette, IN 47907
United States

A. Jeremy Willsey

University of California, San Francisco (UCSF) - Department of Psychiatry

505 Parnassus Ave
San Francisco, CA 94143
United States

Matthew W. State (Contact Author)

University of California, San Francisco (UCSF) - Department of Psychiatry ( email )

505 Parnassus Ave
San Francisco, CA 94143
United States

No contact information is available for Tourette International Collaborative Genetics (TIC Genetics)
No contact information is available for Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE)
No contact information is available for Tourette Association of America International Consortium for Genetics (TAAICG)

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