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

Lookup NU author(s): Professor Naeem Soomro

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Abstract

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.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 metadata

Author(s): Purdue MP, Dutta D, Machiela MJ, Gorman BR, Winter T, Okuhara D, Cleland S, Ferreiro-Iglesias A, Scheet P, Liu A, Wu C, Antwi SO, Larkin J, Zequi SC, Sun M, Hikino K, Hajiran A, Lawson KA, Carcano F, Blanchet O, Shuch B, Nepple KG, Margue G, Sundi D, Diver WR, Folgueira MAAK, van Bokhoven A, Neffa F, Brown KM, Hofmann JN, Rhee J, Yeager M, Cole NR, Hicks BD, Manning MR, Hutchinson AA, Rothman N, Huang W-Y, Linehan WM, Lori A, Ferragu M, Zidane-Marinnes M, Serrano SV, Magnabosco WJ, Vilas A, Decia R, Carusso F, Graham LS, Anderson K, Bilen MA, Arciero C, Pellegrin I, Ricard S, Scelo G, Banks RE, Vasudev NS, Soomro N, Stewart GD, Adeyoju A, Bromage S, Hrouda D, Gibbons N, Patel P, Sullivan M, Protheroe A, Nugent FI, Fournier MJ, Zhang X, Martin LJ, Komisarenko M, Eisen T, Cunningham SA, Connolly DC, Uzzo RG, Zaridze D, Mukeria A, Holcatova I, Hornakova A, Foretova L, Janout V, Mates D, Jinga V, Rascu S, Mijuskovic M, Savic S, Milosavljevic S, Gaborieau V, Abedi-Ardekani B, McKay J, Johansson M, Phouthavongsy L, Hayman L, Li J, Lungu I, Bezerra SM, Souza AG, Sares CTG, Reis RB, Gallucci FP, Cordeiro MD, Pomerantz M, Lee G-SM, Freedman ML, Jeong A, Greenberg SE, Sanchez A, Thompson RH, Sharma V, Thiel DD, Ball CT, Abreu D, Lam ET, Nahas WC, Master VA, Patel AV, Bernhard J-C, Freedman ND, Bigot P, Reis RM, Colli LM, Finelli A, Manley BJ, Terao C, Choueiri TK, Carraro DM, Houlston R, Eckel-Passow JE, Abbosh PH, Ganna A, Brennan P, Gu J, Chanock SJ

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2024

Pages: Epub ahead of print

Online publication date: 26/04/2024

Acceptance date: 13/03/2024

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: . https://doi.org/10.1038/s41588-024-01725-7

DOI: 10.1038/s41588-024-01725-7


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