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Cell Rep. 2018 Sep 25;24(13):3441-3454.e12. 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.

Author information

1
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.
2
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.
3
Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
4
Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
5
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
6
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.
7
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.
8
Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
9
Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
10
Department of Neuroscience, Child and Adolescent Psychiatry Uppsala University, Uppsala, Sweden; Centre for Research and Development, Region Gävleborg, Gävle, Sweden.
11
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
12
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.
13
Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL, USA.
14
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15
Department of Biological Sciences, Purdue University, West Lafayette, IN, USA. Electronic address: ppaschou@purdue.edu.
16
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. Electronic address: jeremy.willsey@ucsf.edu.
17
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. Electronic address: matthew.state@ucsf.edu.

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.

KEYWORDS:

TIC Genetics; Tourette disorder; cell polarity; copy number variants; de novo variants; gene discovery; microarray genotyping; multiplex; simplex; whole exome sequencing

PMID:
30257206
DOI:
10.1016/j.celrep.2018.08.082
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