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Translational genomics and beyond in bipolar disorder

Molecular Psychiatry volume 26, pages 186–202 (2021)Cite this article

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Abstract

Genome-wide association studies (GWAS) have revealed multiple genomic loci conferring risk of bipolar disorder (BD), providing hints for its underlying pathobiology. However, there are still remaining questions to answer. For example, discordance exists between BD heritability estimated with earlier epidemiological evidence and that calculated based on common GWAS variations. Where is the “missing heritability”? How can we explain the biology of the disease based on genetic findings? In this review, we summarize the accomplishments and limitations of current BD GWAS, and discuss potential reasons for the “missing heritability.” In addition, progresses of research for the biological mechanisms underlying BD genetic risk using brain tissues, reprogrammed cells, and model animals are reviewed. While our knowledge of BD genetic basis is significantly promoted by these efforts, the complexities of gene regulation in the genome, the spatial-temporal heterogeneity during brain development, and the limitations of different experimental models should always be considered. Notably, several genes have been widely studied given their relatively well-characterized involvement in BD (e.g., CACAN1C and ANK3), and findings of these genes are summarized to both outline possible biological mechanisms of BD and describe examples of translating GWAS discoveries into the pathophysiology.

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Fig. 1: Efforts in elucidating the genetic architecture of BD.
Fig. 2: Dissecting BD pathogenesis based on genetic discoveries.
Fig. 3: Genetic associations of SNPs spanning CACNA1C region with BD in PGC2 GWAS.

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Acknowledgements

This work is supported by grants from National Key Research and Development Program of China (2018YFC1314302), National Natural Science Foundation of China (81771450 to CZ, 81722019 to ML, 81920108018 to TL), the Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004), special foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001 to TL), and 1.3.5 Project for disciplines of excellence from West China Hospital of Sichuan University (ZY2016103 and ZY2016203 to TL). XX is supported by the Chinese Academy of Sciences Western Light Program, and Youth Innovation Promotion Association, CAS. ML is also supported by CAS Pioneer Hundred Talents Program and the 1000 Young Talents Program.

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  1. These authors contributed equally: Chen Zhang, Xiao Xiao

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  1. Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chen Zhang

  2. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chen Zhang

  3. 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

    Xiao Xiao & Ming Li

  4. Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Tao Li

  5. West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Tao Li

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Zhang, C., Xiao, X., Li, T. et al. Translational genomics and beyond in bipolar disorder. Mol Psychiatry 26, 186–202 (2021). https://doi.org/10.1038/s41380-020-0782-9

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