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

Author

Listed:
  • Xinglun Dang

    (Southeast University)

  • Zhaowei Teng

    (The Second Affiliated Hospital of Kunming Medical University, Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province)

  • Yongfeng Yang

    (The Second Affiliated Hospital of Xinxiang Medical University
    Xinxiang Medical University)

  • Wenqiang Li

    (The Second Affiliated Hospital of Xinxiang Medical University
    Xinxiang Medical University)

  • Jiewei Liu

    (Wuhan Mental Health Center)

  • Li Hui

    (Suzhou Medical College of Soochow University)

  • Dongsheng Zhou

    (Affiliated Kangning Hospital of Ningbo University (Ningbo Kangning Hospital))

  • Daohua Gong

    (Southeast University)

  • Shan-Shan Dai

    (Southeast University)

  • Yifan Li

    (Southeast University)

  • Xingxing Li

    (Affiliated Kangning Hospital of Ningbo University (Ningbo Kangning Hospital))

  • Luxian Lv

    (The Second Affiliated Hospital of Xinxiang Medical University
    Xinxiang Medical University)

  • Yong Zeng

    (The Second Affiliated Hospital of Kunming Medical University, Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province)

  • Yonggui Yuan

    (Southeast University)

  • Xiancang Ma

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Zhongchun Liu

    (Renmin Hospital of Wuhan University
    Wuhan University)

  • Tao Li

    (Zhejiang University School of Medicine)

  • Xiong-Jian Luo

    (Southeast University)

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.

Suggested Citation

  • Xinglun Dang & Zhaowei Teng & Yongfeng Yang & Wenqiang Li & Jiewei Liu & Li Hui & Dongsheng Zhou & Daohua Gong & Shan-Shan Dai & Yifan Li & Xingxing Li & Luxian Lv & Yong Zeng & Yonggui Yuan & Xiancan, 2025. "Gene-level analysis reveals the genetic aetiology and therapeutic targets of schizophrenia," Nature Human Behaviour, Nature, vol. 9(3), pages 609-624, March.
  • Handle: RePEc:nat:nathum:v:9:y:2025:i:3:d:10.1038_s41562-024-02091-4
    DOI: 10.1038/s41562-024-02091-4
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