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Gene-level analysis reveals the genetic aetiology and therapeutic targets of schizophrenia

Nature Human Behaviour volume 9, pages 609–624 (2025)Cite this article

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Abstract

Genome-wide association studies (GWASs) have reported multiple risk loci for schizophrenia (SCZ). However, the majority of the associations were from populations of European ancestry. Here we conducted a large-scale GWAS in Eastern Asian populations (29,519 cases and 44,392 controls) and identified ten Eastern Asian-specific risk loci, two of which have not been previously reported. A further cross-ancestry GWAS meta-analysis (96,806 cases and 492,818 controls) including populations from diverse ancestries identified 61 previously unreported risk loci. Systematic variant-level analysis, including fine mapping, functional genomics and expression quantitative trait loci, prioritized potential causal variants. Gene-level analyses, including transcriptome-wide association study, proteome-wide association study and Mendelian randomization, nominated the potential causal genes. By integrating evidence from layers of different analyses, we prioritized the most plausible causal genes for SCZ, such as ACE, CNNM2, SNAP91, ABCB9 and GATAD2A. Finally, drug repurposing showed that ACE, CA14, MAPK3 and MAPT are potential therapeutic targets for SCZ. Our study not only showed the power of cross-ancestry GWAS in deciphering the genetic aetiology of SCZ, but also uncovered new genetic risk loci, potential causal variants and genes and therapeutic targets for SCZ.

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Fig. 1: Manhattan plots of GWASs.
Fig. 2: TF-binding disrupting SNPs and fine-mapping results.
Fig. 3: Transcriptome-wide and proteome-wide association results.
Fig. 4: Drug targets identified by MR analysis.
Fig. 5: Gene prioritization results.
Fig. 6: SynGO enrichment of high-confidence risk genes.

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Data availability

The genome-wide summary statistics of the SCZ (PGC3) are available via Figshare at https://doi.org/10.6084/m9.figshare.19426775.v6 (ref. 81). The genome-wide summary statistics of the EAS are available via Figshare at https://doi.org/10.6084/m9.figshare.19193084.v1 (ref. 82). The genome-wide summary statistics of the FinnGen are available at https://storage.googleapis.com/finngen-public-data-r9/summary_stats/. The SNP expression weights of PsychENCODE used in this study are available at http://resource.psychencode.org/. The processed protein weight files are available via the Synapse portal (Synapse IDs syn9884314 and syn23245237). The PsychENCODE cis-eQTL data are available via the SMR website at https://yanglab.westlake.edu.cn/data/SMR/PsychENCODE_cis_eqtl_HCP100_summary.tar.gz. The gene expression data used for MAGMA were from the Genotype-Tissue Expression (GTEx) consortium, GTEx_Analysis_2017-06-05_v8_RNASeQCv1.1.9. All Gene Ontology terms (including cellular components, biological processes and molecular functions) and Kyoto Encyclopedia of Genes and Genomes pathway gene sets are available via the MSigDB database at https://www.gsea-msigdb.org/gsea/msigdb/human/collections.jsp#C5. The BrainMeta V2 eQTL data are available via the BrainMeta portal at https://yanglab.westlake.edu.cn/data/SMR/BrainMeta_cis_eqtl_summary.tar.gz. Genome-wide summary statistics for EUR-ancestry meta-analysis of SCZ (59,901 cases and 441,418 controls) and GWAS summary statistics for cross-ancestry meta-analysis of SCZ (excluding the Chinese population, a total of 90,065 cases and 483,788 controls) are available via Figshare at https://doi.org/10.6084/m9.figshare.27313227 (ref. 83). The GWAS dataset for the Chinese population can be requested from the China National Genomics Data Center (https://ngdc.cncb.ac.cn/), with the data accession number OMIX005075.

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Acknowledgements

This study was equally supported by the National Natural Science Foundation of China (U2102205 and U22A20304) and startup funds from Southeast University (RF1028623032). It was also supported by the Special Project for Social Development of Yunnan Province (no. 202203AC100007), Key Research and Development Projects of Henan Province (241111312800 and 235101610004 to W.L.), Intestinal Microbiota Transplantation Engineering Research Center, Yunnan Provincial Department of Education (to Z.T.), the National Natural Science Foundation of China (nos. 82171498, 82230044, 81920108018, U21A20364, 82260276, 82301690, 82371508 and 82371508), the Talent and Fundamental Research Project of Yunnan Province (nos. 202301AY070001-299, 202105AC160004 and 202301AT070037), Key R&D Program of Zhejiang Province (grant number 2022C03096 to T.L.), the Key R & D by Hangzhou Science and Technology Bureau (grant number 20241203A14 to T.L.) and the Construction Fund of Key Medical Disciplines of Hangzhou (OO20200065 to T.L.). We thank Q. Li and Z. Ding for their technical assistance. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Xinglun Dang, Zhaowei Teng, Yongfeng Yang, Wenqiang Li, Jiewei Liu, Li Hui, Dongsheng Zhou.

Authors and Affiliations

  1. Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Jiangsu Provincial Key Laboratory of Brain Science and Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China

    Xinglun Dang, Daohua Gong, Shan-Shan Dai, Yifan Li, Yonggui Yuan & Xiong-Jian Luo

  2. The Second Affiliated Hospital of Kunming Medical University, Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, Kunming, China

    Zhaowei Teng & Yong Zeng

  3. Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China

    Yongfeng Yang, Wenqiang Li & Luxian Lv

  4. Henan Key Lab of Biological Psychiatry, Henan Collaborative Innovation Center of Prevention and Treatment of Mental Disorders, Xinxiang Medical University, Xinxiang, China

    Yongfeng Yang, Wenqiang Li & Luxian Lv

  5. Department of Psychiatry, Wuhan Mental Health Center, Wuhan, China

    Jiewei Liu

  6. Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China

    Li Hui

  7. Department of Psychiatry, Affiliated Kangning Hospital of Ningbo University (Ningbo Kangning Hospital), Ningbo, China

    Dongsheng Zhou & Xingxing Li

  8. Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Xiancang Ma

  9. Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China

    Zhongchun Liu

  10. Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Zhongchun Liu

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

    Tao Li

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Contributions

X.-J.L. conceived, designed and supervised the whole study. X.D. performed most of the analyses. Z.T., Y. Yang, W.L., J.L., L.H., D.Z., X.L., L.L., Y.Z., D.G., S.-S.D., Y.L., Y. Yuan, X.M., Z.L. and T.L. contributed to sample collection, genotyping and paper writing. All authors revised the paper critically and approved the final version.

Corresponding authors

Correspondence to Xiancang Ma, Zhongchun Liu, Tao Li or Xiong-Jian Luo.

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Supplementary Figs. 1–40.

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Supplementary Table 1

Supplementary Tables 1–19.

Source Data Table 1

Statistical source data for Supplementary Figs. 31–39.

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Dang, X., Teng, Z., Yang, Y. et al. Gene-level analysis reveals the genetic aetiology and therapeutic targets of schizophrenia. Nat Hum Behav 9, 609–624 (2025). https://doi.org/10.1038/s41562-024-02091-4

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