Abstract
Genome-wide association studies (GWASs) of bipolar disorder (BD) have predominantly included individuals of European (EUR) ancestry, underrepresenting non-EUR populations and limiting insight into disease mechanisms. Here we performed a GWAS of BD in Han Chinese individuals (5,164 cases and 13,460 controls) and conducted comparative and integrative analyses with independent East Asian (EAS, 4,479 cases and 75,725 controls) and EUR (59,287 cases and 781,022 controls) cohorts from the PGC4 GWAS. Our GWAS in EAS ancestry identified two genome-wide significant risk loci, including variants at the major histocompatibility complex (MHC) class II region. Incorporating EAS data into trans-ancestry GWAS revealed 93 significant loci (23 novel). Heritability enrichment analyses implicated a variety of neuronal cell types. Multidimensional post-GWAS prioritization identified 39 high-confidence risk genes, of which 15 were differentially expressed in the brains of patients with BD, 12 modulated BD-relevant behaviors in mice and 18 are pharmacologically tractable. This work advances understanding of the biological underpinnings of BD and provides direction for future research in underrepresented populations.
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Data availability
The genome-wide summary statistics of BD PGC4 GWAS are available via figshare at https://doi.org/10.6084/m9.figshare.27216117.v2 (ref. 85). The SNP expression weights of PsychENCODE used in this study are available at http://resource.psychencode.org/. The PsychENCODE cis-eQTL data and the BrainMeta version 2 cis-eQTL data are available via the BrainMeta portal at https://yanglab.westlake.edu.cn/software/smr/#DataResource. The cell-type-specific gene expression matrices from two BICCN studies29,30 for enrichment analysis were downloaded from the CELLxGENE database at https://cellxgene.cziscience.com/collections/bacccb91-066d-4453-b70e-59de0b4598cd and https://cellxgene.cziscience.com/collections/283d65eb-dd53-496d-adb7-7570c7caa443 separately. The summary statistics of BD cross-ancestry meta-analysis are publicly available on the Scientific Data Center of the Kunming Institute of Zoology (https://datacenter.kiz.ac.cn/Home/DataContent?data_gd=4c22800a-d798-169c-7184-430976572334). According to the related policy of the Ministry of Science and Technology of the People’s Republic of China, depositing genetic data (including the summary statistics) of Chinese populations in a third-party website (without application) is not allowed before approval; alternatively, GWAS summary statistics in Chinese populations can be requested from the China National Genomics Data Center (https://ngdc.cncb.ac.cn/gvm/), with data accession number GVP000051.
Code availability
No custom code was developed for this study. All software and tools used for the analyses presented are publicly available and referenced within the respective sections in Methods of the article.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (82225016 to Ming Li and 82222024 and U24A20699 to X.X.); the National Key Research and Development Program of China (2023YFA1800500 to Ming Li, 2024YFA1803200 to X.X., 2023YFE0119400 to W.Y. and 2023YFC2605400 to S.X.); the National Natural Science Foundation of China (82230044 to Y.G., U21A20364 to Z.L., 82330042 to W.Y., 81930033 to Y.F., 32030020 to S.X., 32470649 to Y.L. and 323B2013 to X.T.); the Yunnan Fundamental Research Projects (202201AS070048 and 202401AS070080 to Ming Li, 202401AS070084 and 202501AV070009 to X.X. and 202305AH340006 to Y.-G.Y.); the Municipal Key R&D Program of Ningbo (2022Z127 to C.W.); the Jiangsu Provincial Key Research and Development Program (BE2020661 to L.H.); the Spring City Plan: the High-level Talent Promotion and Training Project of Kunming (2022SCP001 to Ming Li); the Shanghai Mental Health Centre Clinical Research Center Major Project (CRC2018ZD02 to Y.F.); the Shanghai Science and Technology Commission Program (23JS1410100 to S.X.); the Chinese Academy of Sciences (CAS) ‘Light of West China’ Program (xbzg-zdsys-202312 to X.X. and xbzg-zdsys-202404 to Ming Li); the Japan Agency for Medical Research and Development (21wm0425008 to N.I.); and the Open Program of Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms (AMHD-2024-2, AMHD-2024-6 and AMHD-2024-8 to Ming Li). X.X. was also supported by the CAS ‘Light of West China’ Program, the CAS Youth Innovation Promotion Association and the Yunnan Revitalization Talent Support Program Young Talent Project. Ming Li was also supported by the Yunnan Revitalization Talent Support Program Yunling Scholar Project. PsychENCODE Consortium data were generated as part of the PsychENCODE Consortium. See https://doi.org/10.7303/syn26365932 for a complete list of grants and principal investigators. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Ming Li and X.X. conceived and designed the study. C.-Y.Z. performed most statistical analyses on the GWAS data, with the help of Miao Li and Y.W. P.S., L.H., Y.G., J.-Z.Y., N.Z., X.F., L.G., J.Y., H.-Y.J., Y.-Q.C., S.M., Q.G., Y.S., Y.L., N.Q., X.-Y.Y., L.W., Y.Y., C.W., L.L., D.Z., X.L., X.C., C.Z., J.C., X.S., J.T., J.C., W.F., Wei Tang, Wenxin Tang, W.L., X.T., X.Z., Y.L., C.W., Z.L., S.X., W.Y., Y.F. and F.Z. contributed to sample collections. The GeseDNA Research Team helped with sample collections. N.I., M.I. and T.S. contributed to the data in the Japanese sample. Y.-G.Y. and H.-C.S. helped with all aspects of study design and results interpretation. Ming Li, X.X. and C.-Y.Z. drafted the first version of the paper. All authors revised the paper critically and approved the final version.
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Zhang, CY., Li, M., Sun, P. et al. Trans-ancestry genome-wide analyses of bipolar disorder in East Asian and European populations improve genetic discovery. Nat Neurosci 29, 293–305 (2026). https://doi.org/10.1038/s41593-025-02147-2
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DOI: https://doi.org/10.1038/s41593-025-02147-2
