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

Mark P. Purdue, Diptavo Dutta, Mitchell J. Machiela, Bryan R. Gorman, Timothy Winter, Dayne Okuhara, Sara Cleland, Aida Ferreiro-Iglesias, Paul Scheet, Aoxing Liu, Chao Wu, Samuel O. Antwi, James Larkin, Stênio C. Zequi, Maxine Sun, Keiko Hikino, Ali Hajiran, Keith A. Lawson, Flavio Cárcano, Odile BlanchetBrian Shuch, Kenneth G. Nepple, Gaëlle Margue, Debasish Sundi, W. Ryan Diver, Maria A.A.K. Folgueira, Adrie van Bokhoven, Florencia Neffa, Kevin M. Brown, Jonathan N. Hofmann, Jongeun Rhee, Meredith Yeager, Nathan R. Cole, Belynda D. Hicks, Michelle R. Manning, Amy A. Hutchinson, Nathaniel Rothman, Wen Yi Huang, W. Marston Linehan, Adriana Lori, Matthieu Ferragu, Merzouka Zidane-Marinnes, Sérgio V. Serrano, Wesley J. Magnabosco, Ana Vilas, Ricardo Decia, Florencia Carusso, Laura S. Graham, Kyra Anderson, Mehmet A. Bilen, Cletus Arciero, Isabelle Pellegrin, Solène Ricard, Ghislaine Scelo, Rosamonde E. Banks, Naveen S. Vasudev, Naeem Soomro, Grant D. Stewart, Adebanji Adeyoju, Stephen Bromage, David Hrouda, Norma Gibbons, Poulam Patel, Mark Sullivan, Andrew Protheroe, Francesca I. Nugent, Michelle J. Fournier, Xiaoyu Zhang, Lisa J. Martin, Maria Komisarenko, Timothy Eisen, Sonia A. Cunningham, Denise C. Connolly, Robert G. Uzzo, David Zaridze, Anush Mukeria, Ivana Holcatova, Anna Hornakova, Lenka Foretova, Vladimir Janout, Dana Mates, Viorel Jinga, Stefan Rascu, Mirjana Mijuskovic, Slavisa Savic, Sasa Milosavljevic, Valérie Gaborieau, Behnoush Abedi-Ardekani, James McKay, Mattias Johansson, Larry Phouthavongsy, Lindsay Hayman, Jason Li, Ilinca Lungu, Stephania M. Bezerra, Aline G. Souza, Claudia T.G. Sares, Rodolfo B. Reis, Fabio P. Gallucci, Mauricio D. Cordeiro, Mark Pomerantz, Gwo Shu M. Lee, Matthew L. Freedman, Anhyo Jeong, Samantha E. Greenberg, Alejandro Sanchez, R. Houston Thompson, Vidit Sharma, David D. Thiel, Colleen T. Ball, Diego Abreu, Elaine T. Lam, William C. Nahas, Viraj A. Master, Alpa V. Patel, Jean Christophe Bernhard, Neal D. Freedman, Pierre Bigot, Rui M. Reis, Leandro M. Colli, Antonio Finelli, Brandon J. Manley, Chikashi Terao, Toni K. Choueiri, Dirce M. Carraro, Richard Houlston, Jeanette E. Eckel-Passow, Philip H. Abbosh, Andrea Ganna, Paul Brennan, Jian Gu, Stephen J. Chanock

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)809-818
Number of pages10
JournalNature Genetics
Volume56
Issue number5
Early online dateMar 26 2024
DOIs
StatePublished - Apr 2024

Keywords

  • 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

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