Cell Reports (Sep 2018)
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis
- Sheng Wang,
- Jeffrey D. Mandell,
- Yogesh Kumar,
- Nawei Sun,
- Montana T. Morris,
- Juan Arbelaez,
- Cara Nasello,
- Shan Dong,
- Clif Duhn,
- Xin Zhao,
- Zhiyu Yang,
- Shanmukha S. Padmanabhuni,
- Dongmei Yu,
- Robert A. King,
- Andrea Dietrich,
- Najah Khalifa,
- Niklas Dahl,
- Alden Y. Huang,
- Benjamin M. Neale,
- Giovanni Coppola,
- Carol A. Mathews,
- Jeremiah M. Scharf,
- Thomas V. Fernandez,
- Joseph D. Buxbaum,
- Silvia De Rubeis,
- Dorothy E. Grice,
- Jinchuan Xing,
- Gary A. Heiman,
- Jay A. Tischfield,
- Peristera Paschou,
- A. Jeremy Willsey,
- Matthew W. State
Affiliations
- Sheng Wang
- College of Biological Sciences, China Agricultural University, Beijing, China; National Institute of Biological Sciences, Beijing, China; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Jeffrey D. Mandell
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Yogesh Kumar
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
- Nawei Sun
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Montana T. Morris
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Juan Arbelaez
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Cara Nasello
- Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
- Shan Dong
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Clif Duhn
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Xin Zhao
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Traditional Chinese Medicine, Xinhua Hospital Affiliated to Shanghai Jiatong University School of Medicine, Shanghai, China
- Zhiyu Yang
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
- Shanmukha S. Padmanabhuni
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
- Dongmei Yu
- Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Robert A. King
- Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- Andrea Dietrich
- Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Najah Khalifa
- Department of Neuroscience, Child and Adolescent Psychiatry Uppsala University, Uppsala, Sweden; Centre for Research and Development, Region Gävleborg, Gävle, Sweden
- Niklas Dahl
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Alden Y. Huang
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA
- Benjamin M. Neale
- Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Giovanni Coppola
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA
- Carol A. Mathews
- Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL, USA
- Jeremiah M. Scharf
- Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Thomas V. Fernandez
- Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- Joseph D. Buxbaum
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Silvia De Rubeis
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Dorothy E. Grice
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Jinchuan Xing
- Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
- Gary A. Heiman
- Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
- Jay A. Tischfield
- Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
- Peristera Paschou
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA; Corresponding author
- A. Jeremy Willsey
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; Corresponding author
- Matthew W. State
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; Corresponding author
- Journal volume & issue
-
Vol. 24,
no. 13
pp. 3441 – 3454.e12
Abstract
Summary: 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. Keywords: Tourette disorder, simplex, multiplex, de novo variants, copy number variants, whole exome sequencing, microarray genotyping, gene discovery, cell polarity, TIC Genetics
