Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions

Nat Genet. 2024 May;56(5):809-818. doi: 10.1038/s41588-024-01725-7. Epub 2024 Apr 26.

Abstract

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.

Publication types

  • Meta-Analysis

MeSH terms

  • Black People
  • Carcinoma, Renal Cell* / genetics
  • Case-Control Studies
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Humans
  • Kidney Neoplasms* / genetics
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • White People / genetics

Substances

  • Von Hippel-Lindau Tumor Suppressor Protein