In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; Pcombined = 6.2 × 10−34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.
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Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000).
Amundadottir, L.T. et al. Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. PLoS Med. 1, e65 (2004).
Ewing, C.M. et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl. J. Med. 366, 141–149 (2012).
Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).
Gudmundsson, J. et al. Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat. Genet. 44, 319–322 (2012).
Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).
Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).
Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).
Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).
Haiman, C.A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet. 39, 638–644 (2007).
Zheng, S.L. et al. Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J. Natl. Cancer Inst. 99, 1525–1533 (2007).
Gudmundsson, J. et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).
Yeager, M. et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41, 1055–1057 (2009).
Al Olama, A.A. et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat. Genet. 41, 1058–1060 (2009).
Crowther-Swanepoel, D. et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).
Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).
Zanke, B.W. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat. Genet. 39, 989–994 (2007).
Haiman, C.A. et al. A common genetic risk factor for colorectal and prostate cancer. Nat. Genet. 39, 954–956 (2007).
Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).
Kiemeney, L.A. et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).
Witte, J.S. Multiple prostate cancer risk variants on 8q24. Nat. Genet. 39, 579–580 (2007).
Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).
Kong, A. et al. Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467, 1099–1103 (2010).
Sulem, P. et al. Identification of low-frequency variants associated with gout and serum uric acid levels. Nat. Genet. 43, 1127–1130 (2011).
Rafnar, T. et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 43, 1104–1107 (2011).
Stacey, S.N. et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat. Genet. 43, 1098–1103 (2011).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
We thank the individuals who participated in the study and whose contribution made this work possible. This project was funded in part by contract number 202059 (PROMARK) from the Seventh Framework Programme of the European Union and, in part, by the Urological Research Foundation (U01 CA089600, P50 CA90386 and P30 CA60553). The UK ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06 and 96/20/99). The ProtecT trial is supported by the Department of Health, England; Cancer Research UK grant C522/A8649; Medical Research Council of England grant G0500966_ID-75466; the National Cancer Research Institute (NCRI), UK; and the Southwest National Health Service Research and Development. The biorepository from ProtecT is supported by the NCRI (ProMPT) study and Cambridge and Oxford British Medical Research Council grants from the National Institute for Health Research.
The authors from deCODE Genetics declare competing financial interests: all are employees of the company, and some are shareholders.
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Gudmundsson, J., Sulem, P., Gudbjartsson, D. et al. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44, 1326–1329 (2012). https://doi.org/10.1038/ng.2437
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