Dang Xinglun, Teng Zhaowei, Yang Yongfeng, Li Wenqiang, Liu Jiewei, Hui Li, Zhou Dongsheng, Gong Daohua, Dai Shan-Shan, Li Yifan, Li Xingxing, Lv Luxian, Zeng Yong, Yuan Yonggui, Ma Xiancang, Liu Zhongchun, Li Tao, Luo Xiong-Jian
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.
The Second Affiliated Hospital of Kunming Medical University, Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, Kunming, China.
Nat Hum Behav. 2025 Mar;9(3):609-624. doi: 10.1038/s41562-024-02091-4. Epub 2025 Jan 3.
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.
全基因组关联研究（GWAS）已报告了精神分裂症（SCZ）的多个风险位点。然而，大多数关联来自欧洲血统人群。在此，我们在东亚人群（29519例病例和44392例对照）中开展了一项大规模GWAS，并鉴定出10个东亚特异性风险位点，其中两个此前未被报告。进一步的跨血统GWAS荟萃分析（96806例病例和492818例对照）纳入了来自不同血统的人群，鉴定出61个此前未报告的风险位点。系统的变异水平分析，包括精细定位、功能基因组学和表达定量性状位点分析，对潜在的因果变异进行了优先级排序。基因水平分析，包括全转录组关联研究、全蛋白质组关联研究和孟德尔随机化分析，提名了潜在的因果基因。通过整合来自不同分析层面的证据，我们确定了SCZ最有可能的因果基因，如ACE、CNNM2、SNAP91、ABCB9和GATAD2A。最后，药物再利用研究表明，ACE、CA14、MAPK3和MAPT是SCZ的潜在治疗靶点。我们的研究不仅展示了跨血统GWAS在解读SCZ遗传病因方面的能力，还发现了新的遗传风险位点、潜在因果变异、基因以及SCZ的治疗靶点。
