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Mutations in ASH1L confer susceptibility to Tourette syndrome

Molecular Psychiatry volume 25, pages 476–490 (2020)Cite this article

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Abstract

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/− mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

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Data availability

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request. All relevant data will be deposited into a public repository and accession codes will be available before publication.

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Acknowledgements

We thank Richard A Gibbs, Huda Zoghbi, and Sau Wai Cheung for constructive suggestions. We are grateful to all of the patients and their families for participating in this study. We thank Dr. Yulong Li for the DA sensor virus and Dr. Yi Qian, Dr. Lianhui Zhu and Dr. Haopeng Wang for suggestions on ELISA assay. The work is supported by grants from the National Natural Science Foundation (NSFC) (81371499, 31671104, 81471365, 31970903, and 31371059), the National Key Research and Development Program of China (2016YFC1000307), National Basic Research Program of China (2013CB835100), Beijing Municipal Education Commission  “scientific research base - technology innovation platform - the construction of major brain disease laboratory platform” and “subject group - clinical medicine” (BIBD-PXM2013_014226_07_000084), and Beijing Natural Science Foundation (7132083). Shandong Provincial Natural Science Foundation of China (ZR2019PH072). The work was partially funded by the NSFC and the German Research Foundation (DFG) in project Cross model Learning, NSFC (61621136008)/DGF TRR-169 to J-SG. JL and FY were supported by the National Institutes of Health and National Human Genome Research Institute (R01HG008115 awarded to FY). Dr. Schaaf’s work is generously supported by the Joan and Stanford Alexander Family.

Author information

Author notes

  1. Tao Zhu

    Present address: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China

  2. These authors contributed equally: Shiguo Liu, Miaomiao Tian, Fan He, Jiani Li, Hong Xie

Authors and Affiliations

  1. Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China

    Shiguo Liu, Wenmiao Liu, Ru Zhang, Yinglei Xu, Jingli Wang, Yucui Zang, Mengmeng Han & Xiangrong Sun

  2. The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China

    Shiguo Liu, Wenmiao Liu, Ru Zhang, Yinglei Xu, Jingli Wang, Yucui Zang, Mengmeng Han & Xiangrong Sun

  3. School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China

    Miaomiao Tian, Tao Zhu, Wenhan Luo & Yuze Yan

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Miaomiao Tian, Hong Xie, Wenhan Luo, Qinan Chen, Yuze Yan & Ji-Song Guan

  5. The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China

    Fan He, Yi Zheng, Huanhuan Huang, Yanzhao Wei & Chuanyue Wang

  6. Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Jiani Li & Fuli Yu

  7. Institute of Brain-Intelligence Technology, Zhangjiang Laboratory & Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China

    Hong Xie

  8. Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    Yeting Zhang & Jinchuan Xing

  9. Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China

    Mingji Yi, Ni Ran, Zhaochuan Yang, Xueying Feng & Yixia Guo

  10. Department of Neurology, Linyi People’s Hospital, Linyi, China

    Fengyuan Che

  11. National Research Institute for Family Planning, Beijing, China

    Xu Ma

  12. Center for Experimental Medicine & Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China

    Hao Deng

  13. Child Healthcare Department, Rizhao people’s Hospital, Rizhao, China

    Guiju Wang

  14. Department of Pediatrics, Fujian Provincial Hospital, Provincial Clinical Medical College Affiliated to Fujian Medical University, Fuzhou, China

    Lang Chen

  15. Department of Medical Record, The Affiliated Hospital of Qingdao University, Qingdao, China

    Xue Sun

  16. Department of Biology, Qingdao University, Qingdao, China

    Xiuhai Wang

  17. Department of Clinical Laboratory Diagnosis, Qingdao University, Qingdao, China

    Hongzai Guan & Chunmei Wu

  18. Department of Biochemistry and Molecular Biology, Qingdao University, Qingdao, China

    Yinlin Ge

  19. Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China

    Haiyan Wang, Zuzhou Huang & Zhongcui Jing

  20. Department of Public Health, Qingdao University, Qingdao, China

    Hui Liang

  21. Physical Examination Center, The Affiliated Hospital of Qingdao University, Qingdao, China

    Hui Li & Xuzhan Zhang

  22. Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China

    Xueping Zheng

  23. Department of Psychiatry, The Third Hospital of Chaoyang District of Beijing, Beijing, China

    Lanlan Zheng

  24. Department of Molecular and Human Genetics, Baylor College of Medicine, Department of Genetics; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Christian P. Schaaf

  25. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Ji-Song Guan

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  1. Shiguo Liu
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  2. Miaomiao Tian
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  11. Xu Ma
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Corresponding authors

Correspondence to Chuanyue Wang, Fuli Yu or Ji-Song Guan.

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Liu, S., Tian, M., He, F. et al. Mutations in ASH1L confer susceptibility to Tourette syndrome. Mol Psychiatry 25, 476–490 (2020). https://doi.org/10.1038/s41380-019-0560-8

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