Abstract
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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Acknowledgements
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.
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The study was designed and results were interpreted by J.G., P.S., A.K., U.T., T.R. and K.S. Statistical analysis was carried out by P.S., D.F.G., G.T., J.G. and A.K. Subject recruitment, biological material collection and handling, and genotyping were supervised and carried out by J.G., B.A.A., K.R.B., S.N.S., A.S., O.T.M., S.A.G., D.N.M., H.J., H.T.H., A.J., S.B.O., J.G.J., L.T., S.N., F.F., B.T.H., Q.H., I.E.C., I.N.M., V.J., K.K.H.A., I.M.v.O., S.H.V., J.L.D., F.C.H., C.-F.N., P.K.F.C., K.-M.L., M.C.Y.N., J.R.G., G.M., W.J.C., J.I.M., G.V.E., R.B.B., E.J., D.M., D.E.N., L.A.K., U.T. and T.R. The manuscript was drafted by J.G., P.S., T.R. and K.S. All authors contributed to the final version of the paper. Principal investigators and corresponding authors for the respective replication study populations are: L.A.K., The Netherlands; J.I.M., Spain; D.M., Romania; W.J.C., Chicago; C.-F.N. and M.C.Y.N., Hong Kong; and F.C.H., J.L.D. and D.E.N., the UK.
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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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DOI: https://doi.org/10.1038/ng.2437
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