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

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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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.

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

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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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