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Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

Molecular Psychiatry volume 26, pages 6937–6951 (2021)Cite this article

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Abstract

Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.

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Fig. 1: Overall study design.
Fig. 2: Information used for variant and gene prioritization.
Fig. 3: Protein–protein interaction (PPI) networks.

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Acknowledgements

We thank the families who have participated in and contributed to this study. We are also grateful to the NJCTS for facilitating the inception and organization of the TIC Genetics study. This study was supported by a grant from the National Institute of Mental Health (R01MH092293 to GAH and JAT) and by a grant from the New Jersey Center for Tourette Syndrome (to GAH and JAT). This study was also supported by grants from the National Institute of Mental Health (K08MH099424 to TVF) and the National Institute for Environmental Health Science (R01 ES021462 for YSK and BLL). PM has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña, and the Jaques and Gloria Gossweiler Foundation. AM has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. AM has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1, and FOR 2698). AJW received a Young Investigator Award from Tourette Association of America. IH declares that all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Tourette International Collaborative Genetics Study (TIC Genetics)

Mohamed Abdulkadir1,2,3, Lawrence W. Brown12, Xiaolong Cao1, Barbara J. Coffey13, Li Deng1,2, Andrea Dietrich3, Thomas V. Fernandez4,5, Blanca Garcia-Delgar6, Donald L. Gilbert14, Julie Hagstrøm7, Tammy Hedderly15, Gary A. Heiman1,2, Isobel Heyman16, Pieter J. Hoekstra3, Chaim Huyser17, Eunjoo Kim18, Young-Shin Kim19, Robert A. King4, Justin Koesterich1,2, Yun-Joo Koh20, Samuel Kuperman8, Bennett L. Leventhal21, Marcos Madruga-Garrido22, Athanasios Maras23, Pablo Mir24,25, Astrid Morer6,9,10, Alexander Münchau26, Cara Nasello1,2, Kerstin J. Plessen7,11, Veit Roessner27, Dong-Ho Song28, Matthew W. State13, Joshua K. Thackray1,2, Jay A. Tischfield1,2, A. Jeremy Willsey13,29, Jinchuan Xing1,2, Yeting Zhang1,2, Lisheng Zhou1, Samuel H. Zinner30

Author information

Author notes

  1. These authors contributed equally: Xiaolong Cao, Yeting Zhang

Authors and Affiliations

  1. Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    Xiaolong Cao, Yeting Zhang, Mohamed Abdulkadir, Li Deng, Justin Koesterich, Cara Nasello, Joshua K. Thackray, Lisheng Zhou, Xiaolong Cao, Jay A. Tischfield, Gary A. Heiman & Jinchuan Xing

  2. Human Genetic Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    Xiaolong Cao, Yeting Zhang, Mohamed Abdulkadir, Li Deng, Justin Koesterich, Cara Nasello, Joshua K. Thackray, Jay A. Tischfield, Gary A. Heiman & Jinchuan Xing

  3. Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Mohamed Abdulkadir, Pieter J. Hoekstra & Andrea Dietrich

  4. Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA

    Thomas V. Fernandez & Robert A. King

  5. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Thomas V. Fernandez

  6. Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain

    Blanca Garcia-Delgar & Astrid Morer

  7. Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark, Denmark

    Julie Hagstrøm & Kerstin J. Plessen

  8. Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Samuel Kuperman

  9. Institut d’Investigacions Biomediques August Pi i Sunyer (IDIPABS), Barcelona, Spain

    Astrid Morer

  10. Centro de Investigacion en Red de Salud Mental (CIBERSAM), Instituto Carlos III, Madrid, Spain

    Astrid Morer

  11. Division of Child and Adolescent Psychiatry, University Hospital Lausanne, Lausanne, Switzerland

    Kerstin J. Plessen

  12. Pediatric Neuropsychiatry Program, Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Lawrence W. Brown

  13. Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    Barbara J. Coffey, Matthew W. State & A. Jeremy Willsey

  14. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Donald L. Gilbert

  15. Evelina London Children’s Hospital GSTT, Kings Health Partners AHSC, London, UK

    Tammy Hedderly

  16. Tic Disorder Clinic, Great Ormond Street Hospital for Children NHS Trust, London, UK

    Isobel Heyman

  17. Levvel, specialists for Youth and Families, Amsterdam, The Netherlands

    Chaim Huyser

  18. Department of Psychiatry, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Eunjoo Kim

  19. Department of Psychiatry & Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    Young-Shin Kim

  20. Korea Institute for Children’s Social Development and Rudolph Child Research Center, Seoul, South Korea

    Yun-Joo Koh

  21. University of California San Francisco Medical Center, San Francisco, CA, USA

    Bennett L. Leventhal

  22. Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

    Marcos Madruga-Garrido

  23. Yulius Academy, Yulius Mental Health Organization, Dordrecht, The Netherlands

    Athanasios Maras

  24. Unidad de Trastornos del Movimiento. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

    Pablo Mir

  25. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Pablo Mir

  26. Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany

    Alexander Münchau

  27. Department of Child and Adolescent Psychiatry, TU Dresden, Dresden, Germany

    Veit Roessner

  28. Yonsei University, Severance Hospital, Seoul, South Korea

    Dong-Ho Song

  29. Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA

    A. Jeremy Willsey

  30. Department of Pediatrics, Division of Developmental Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Samuel H. Zinner

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  1. Xiaolong Cao
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  2. Yeting Zhang
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  4. Li Deng
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Consortia

Tourette International Collaborative Genetics Study (TIC Genetics)

  • Mohamed Abdulkadir
  • , Lawrence W. Brown
  • , Xiaolong Cao
  • , Barbara J. Coffey
  • , Li Deng
  • , Andrea Dietrich
  • , Thomas V. Fernandez
  • , Blanca Garcia-Delgar
  • , Donald L. Gilbert
  • , Julie Hagstrøm
  • , Tammy Hedderly
  • , Gary A. Heiman
  • , Isobel Heyman
  • , Pieter J. Hoekstra
  • , Chaim Huyser
  • , Eunjoo Kim
  • , Young-Shin Kim
  • , Robert A. King
  • , Justin Koesterich
  • , Yun-Joo Koh
  • , Samuel Kuperman
  • , Bennett L. Leventhal
  • , Marcos Madruga-Garrido
  • , Athanasios Maras
  • , Pablo Mir
  • , Astrid Morer
  • , Alexander Münchau
  • , Cara Nasello
  • , Kerstin J. Plessen
  • , Veit Roessner
  • , Dong-Ho Song
  • , Matthew W. State
  • , Joshua K. Thackray
  • , Jay A. Tischfield
  • , A. Jeremy Willsey
  • , Jinchuan Xing
  • , Yeting Zhang
  • , Lisheng Zhou
  •  & Samuel H. Zinner

Corresponding author

Correspondence to Jinchuan Xing.

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Conflict of interest

BJC received research support from NIMH, Emalex, and Teva/Nuvelution; honoraria from American Academy of Child and Adolescent Psychiatry, Harvard Medical School/Psychiatry Academy, and Partners Healthcare. BJC served on the advisory board of Skyland Trail and Teva/Nuvelution, and the following roles at the Tourette Association of America: Co-Chair, Medical Advisory Board; TAA-CDC Partnership. VR has served as advisor or consultancy role for Lilly, Novartis, and Shire, and received conference attendance support or was paid for public speaking by Actelion, Lilly, Medice, Novartis and Shire.

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Members of the Tourette International Collaborative Genetics Study (TIC Genetics) are listed below Acknowledgements.

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Cao, X., Zhang, Y., Abdulkadir, M. et al. Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families. Mol Psychiatry 26, 6937–6951 (2021). https://doi.org/10.1038/s41380-021-01094-1

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