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Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings

Molecular Psychiatry volume 27, pages 2927–2939 (2022)Cite this article

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Abstract

Genome-wide association studies (GWAS) have reported substantial genomic loci significantly associated with clinical risk of bipolar disorder (BD), and studies combining techniques of genetics, neuroscience, neuroimaging, and pharmacology are believed to help tackle clinical problems (e.g., identifying novel therapeutic targets). However, translating findings of psychiatric genetics into biological mechanisms underlying BD pathogenesis remains less successful. Biological impacts of majority of BD GWAS risk loci are obscure, and the involvement of many GWAS risk genes in this illness is yet to be investigated. It is thus necessary to review the progress of applying BD GWAS risk genes in the research and intervention of the disorder. A comprehensive literature search found that a number of such risk genes had been investigated in cellular or animal models, even before they were highlighted in BD GWAS. Intriguingly, manipulation of many BD risk genes (e.g., ANK3, CACNA1C, CACNA1B, HOMER1, KCNB1, MCHR1, NCAN, SHANK2 etc.) resulted in altered murine behaviors largely restoring BD clinical manifestations, including mania-like symptoms such as hyperactivity, anxiolytic-like behavior, as well as antidepressant-like behavior, and these abnormalities could be attenuated by mood stabilizers. In addition to recapitulating phenotypic characteristics of BD, some GWAS risk genes further provided clues for the neurobiology of this illness, such as aberrant activation and functional connectivity of brain areas in the limbic system, and modulated dendritic spine morphogenesis as well as synaptic plasticity and transmission. Therefore, BD GWAS risk genes are undoubtedly pivotal resources for modeling this illness, and might be translational therapeutic targets in the future clinical management of BD. We discuss both promising prospects and cautions in utilizing the bulk of useful resources generated by GWAS studies. Systematic integrations of findings from genetic and neuroscience studies are called for to promote our understanding and intervention of BD.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81971259 to ML, 82071275 to XX, 31872778 and 82171506 to ZH, 81930033 to YF); Yunnan Fundamental Research Project (202101AW070020 to XX); Nature Science Foundation of China Key Project (81630030 and 81920108018 to TL); Special Foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001 to TL and YF/JC); the Clinical Research Center of Shanghai Mental Health Center Key Project (CRC2018ZD02 to YF); Project for Hangzhou Medical Disciplines of Excellence and Key Project for Hangzhou Medical Disciplines (202004A11 to TL); National Key Research and Development Program of China (2016YFC1307100 to YF); the Western Light Innovative Research Team of Chinses Academy of Sciences. XX was also supported by the Chinese Academy of Sciences Western Light Program. ML was also supported by CAS Pioneer Hundred Talents Program and the 1000 Young Talents Program. ZH was also supported by Xiangya Hospital Start-up Research Grants, Key Research and Development Program from Hunan Province 2021DK2001 and the innovative team program 2019RS1010 from Department of Science & Technology of Hunan Province, the innovation-driven team project 2020CX016 from Central South University, 111 Grant (B13036), and Hunan 100 Talents Program. We would like to apologize to those authors whose work were not cited or elaborately represented in this review due to space constraints.

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Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Ming Li & Xiao Xiao

  2. Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Ming Li & Tao Li

  3. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Ming Li

  4. Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China

    Tao Li

  5. Clinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jun Chen & Yiru Fang

  6. Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  7. Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  8. Hunan Provincial Clinical Research Center for Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  9. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  10. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  11. Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  12. National Clinical Research Center on Mental Disorders, Changsha, Hunan, China

    Zhonghua Hu

  13. Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China

    Yiru Fang

Authors
  1. Ming Li
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  2. Tao Li
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  3. Xiao Xiao
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  4. Jun Chen
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  5. Zhonghua Hu
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  6. Yiru Fang
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Contributions

ML oversaw the project. ML, YF, TL, and ZH conceived and designed the study, drafted the first version of the manuscript. XX and JC contributed to discussion and preparation of the manuscript. All authors revised the manuscript critically and approved the final version.

Corresponding authors

Correspondence to Ming Li, Tao Li, Zhonghua Hu or Yiru Fang.

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The authors declare no competing interests.

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Li, M., Li, T., Xiao, X. et al. Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings. Mol Psychiatry 27, 2927–2939 (2022). https://doi.org/10.1038/s41380-022-01523-9

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  • DOI: https://doi.org/10.1038/s41380-022-01523-9

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