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Genetic evidence for the “dopamine hypothesis of bipolar disorder”

Molecular Psychiatry volume 28, pages 532–535 (2023)Cite this article

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Bipolar disorder (BD) is a severe psychiatric illness characterized by recurrent episodes of mania/hypomania and depression. Based on the investigations into the pathological and physiological features of BD (e.g., postmortem brain transcriptomes, neuroimaging and neuropathology signatures, genetic and biochemical marks) in patients, several etiological hypotheses have been proposed for this disorder, such as mitochondrial dysfunction, dendritic spine pathology, dysregulated calcium signaling and neurotransmission [1,2,3]. Notably, a review published in this journal has described the “dopamine hypothesis of BD” [4], with evidence obtained from pharmacological, neuroimaging, and postmortem studies. Our study herein provides additional genetic evidence for this pathological hypothesis.

Accumulating studies have suggested substantial contribution of genetic factors in BD, and the Psychiatric Genomics Consortium (PGC) has conducted multiple-stage genome-wide association studies (GWAS) in European populations that provided evidence supporting several pathological hypotheses, either canonical or novel [5, 6]. However, genetic analyses in other ethnic groups are still necessary given the varied genetic architectures and heterogeneity between different populations [7]. We previously conducted a BD GWAS in Han Chinese population including 1822 cases and 4650 controls, followed by an independent replication analysis in 958 cases and 2050 controls [8]. This study identified a genome-wide risk locus in Han Chinese near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; p = 2.49 × 10−8, odds ratio [OR] = 0.650 for T-allele), and a suggestive locus within the gene encoding dopamine receptor D2 (DRD2, rs4245147; p = 3.98 × 10−7; OR = 1.267 for T-allele) [8]. We also examined these two Han Chinese risk SNPs in European populations using the PGC phase 2 BD GWAS data (20,352 BD cases and 31,358 controls, referred to as PGC2 GWAS) [5], and found that rs9863544 did not show evidence of association (p = 0.233, OR = 1.016), while rs4245147 exhibited nominal significance (p = 0.0198, OR = 1.032).

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Fig. 1: Molecular characterization of rs4245147 and rs4936272.

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Acknowledgements

This work was supported by grants from the Yunnan Fundamental Research Projects (202101AW070020 to XX, 202101AT070359 to LW); Natural Science Funds for Distinguished Young Scholar of Zhejiang (LR20H090001 to CW); Municipal Key R&D Program of Ningbo (2022Z127 to CW); Nature Science Foundation of China Key Project (81920108018 to TL); Key R&D Program of Zhejiang (2022C03096 to TL); Special Foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001 to TL); 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 (2018YFC1314600 to ZL); and Open Research Fund (AMHD-2021-1 and AMHD-2022-1).

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Author notes

  1. These authors contributed equally: Chu-Yi Zhang, Xin Cai.

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

    Chu-Yi Zhang, Xin Cai, Lu Wang, Xiong-Jian Luo, Ming Li & Xiao Xiao

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Chu-Yi Zhang & Xin Cai

  3. Department of Pharmacology and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, China

    Lei Guo & Chuang Wang

  4. Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan, Hubei, China

    Zhongchun Liu

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

    Tao Li

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

    Tao Li

  7. Beijing Gese Technology Co., Ltd, Beijing, China

    Zenan Dou, Shan Guan, Tingting Guo, Qinglan Liu, Hoyin Lo & Leilei Zhang

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  1. Chu-Yi Zhang
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GeseDNA Research Team

  • Zenan Dou
  • , Shan Guan
  • , Tingting Guo
  • , Qinglan Liu
  • , Hoyin Lo
  •  & Leilei Zhang

Contributions

XX, CW, TL, ML and CYZ conceived and designed the study. CYZ and ML performed most analyses. XC conducted dual luciferase assays. LG, CW, TL and ZL contributed to sample collections. GeseDNA Research Team helped sample collections. LW and ML contributed to sample organization, DNA extraction and genotyping assays. XJL helped all aspects of study designs and results interpretation. XX, ML and CYZ drafted the first version of the manuscript. All authors revised the manuscript critically and approved the final version.

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Correspondence to Chuang Wang, Tao Li or Xiao Xiao.

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Zhang, CY., Cai, X., Guo, L. et al. Genetic evidence for the “dopamine hypothesis of bipolar disorder”. Mol Psychiatry 28, 532–535 (2023). https://doi.org/10.1038/s41380-022-01808-z

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