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

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, Xiancang Ma (), Zhongchun Liu (), Tao Li () and Xiong-Jian Luo ()
Additional contact information
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
Wenqiang Li: The Second Affiliated Hospital of 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
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
Tao Li: Zhejiang University School of Medicine
Xiong-Jian Luo: Southeast University

Nature Human Behaviour, 2025, vol. 9, issue 3, 609-624

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41562-024-02091-4

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