Renal cell carcinoma (RCC) is the most common type of kidney cancer, but its genetic architecture has not been fully characterized, particularly in Asian populations. Here, we perform a multi-ancestry meta-analysis of 33,712 RCC cases and 845,786 controls, including individuals of East Asian (5,313 cases and 96,912 controls), European (25,890 cases and 743,585 controls), African American (897 cases and 3,109 controls), and Latin American ancestry (1,612 cases and 2,180 controls), which unveils 10 novel RCC-associated loci and a Chinese-specific locus at 12p13. 33. Leveraging genome-wide association study (GWAS) data and cross-ancestry expression quantitative trait loci (eQTLs) mapping from 266 kidney tissues, we refine the identification of putative causal variants and genes implicated in RCC. These findings are substantiated through CRISPR-based screenings and multiplexed single-cell perturbations. Additionally, we functionally validate a novel association between rs28684409 and the oncogene RPL4 at the complex genetic locus 15q22.31. This comprehensive genetic investigation underscores the utility of integrating cross-ancestry GWASs, QTLs, and functional screens to elucidate the genetic underpinnings of complex diseases.
Nature communications. 2026 Apr 18 [Epub ahead of print]
Hongji Dai, Xinlei Chu, Han Du, Shutong Yang, Yanxin Yao, Xinru Yu, Yanrui Zhao, Pei Dong, Zhangyan Lyu, Wei Wang, Haixin Li, Zeyun Mi, Chao Sheng, Xiangchun Li, Hong Zheng, Fangfang Song, Fengju Song, Menghong Sun, Juncheng Dai, Qing Lan, Nathaniel Rothman, Zhibin Hu, Qingyi Wei, Dingwei Ye, Xin Yao, Weihua Jia, Stephen J Chanock, Hongbing Shen, Mark P Purdue, Mulin Jun Li, Kexin Chen
Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China., Department of Urology Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China., Tianjin Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China., Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China., Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Institute for Cancer Prevention and Precision Medicine, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China., Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. ., Tianjin Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. ., State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. ., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. ., Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. ., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. ., Key Laboratory of Prevention and Control of Human Major Diseases (Ministry of Education), Tianjin, China. ., Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. .