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<p>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 <i>RPL4</i> 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.</p>

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Genetic landscape and functional exploration of kidney cancer predisposition in cross-ancestral populations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • 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

摘要

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.