Letter | Published:

Multiple regions within 8q24 independently affect risk for prostate cancer


After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 × 10−19 for the strongest association, and P < 1.5 × 10−4 for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Freedman, M.L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl. Acad. Sci. USA 103, 14068–14073 (2006).

  2. 2

    Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).

  3. 3

    de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

  4. 4

    van Duin, M. et al. High-resolution array comparative genomic hybridization of chromosome arm 8q: evaluation of genetic progression markers for prostate cancer. Genes Chromosom. Cancer 44, 438–449 (2005).

  5. 5

    Visakorpi, T. et al. Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res. 55, 342–347 (1995).

  6. 6

    Kolonel, L.N. et al. A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am. J. Epidemiol. 151, 346–357 (2000).

  7. 7

    John, E.M., Schwartz, G.G., Koo, J., Van Den Berg, D. & Ingles, S. Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer. Cancer Res. 65, 5470–5479 (2005).

  8. 8

    Oakley-Girvan, I. et al. Risk of early-onset prostate cancer in relation to germline polymorphisms of the vitamin D receptor. Cancer Epidemiol. Biomarkers Prev. 13, 1325–1330 (2004).

  9. 9

    Cooney, K.A. et al. Age-specific distribution of serum prostate-specific antigen in a community-based study of African-American men. Urology 57, 91–96 (2001).

  10. 10

    Cooney, K.A. et al. Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. J. Natl. Cancer Inst. 89, 955–959 (1997).

  11. 11

    The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  12. 12

    Hosono, S. et al. Unbiased whole-genome amplification directly from clinical samples. Genome Res. 13, 954–964 (2003).

  13. 13

    Fan, J.B. et al. Highly parallel SNP genotyping. Cold Spring Harb. Symp. Quant. Biol. 68, 69–78 (2003).

  14. 14

    Tang, K. et al. Chip-based genotyping by mass spectrometry. Proc. Natl. Acad. Sci. USA 96, 10016–10020 (1999).

  15. 15

    Lee, L.G., Connell, C.R. & Bloch, W. Allelic discrimination by nick-translation PCR with fluorogenic probes. Nucleic Acids Res. 21, 3761–3766 (1993).

  16. 16

    Patterson, N. et al. Methods for high-density admixture mapping of disease genes. Am. J. Hum. Genet. 74, 979–1000 (2004).

  17. 17

    Breslow, N.E. & Day, N.E. Statistical Methods in Cancer Research, Vol 1: the Analysis of Case-Control Studies (International Agency on Cancer Research, Lyon, 1980).

Download references


We thank the men with and without prostate cancer who volunteered to participate in this study. We thank E. Lander, A. Price, J. Seidman and E. Ziv for critical comments and researchers from the NCI Cancer Genetic Markers of Susceptibility Study (CGEMS) Project, whose online data we cited to provide confirmation of the association at rs6983267. Genotyping and personnel were supported by NIH grants CA63464 to B.E.H., C.A.H., D.A., M.L.F. and D.R. and by funds from the Harvard Medical School Department of Genetics (D.R.). M.L.F. was supported by a Department of Defense Health Disparity Training-Prostate Scholar Award (17-02-1-0246) and Dana-Farber/Harvard Partners Cancer Care Prostate SPORE. N.P. was supported by NIH career transition award HG02758. S.C.G. is a Hospital for Sick Children and March of Dimes Fellow of the Pediatric Scientist Development Program, and is also supported by NICHD grant HD00850. C.A.H., D.O.S., M.C.P., L.L.M., L.N.K. and B.E.H. were supported by CA54281, E.M.J. and S.A.I. were supported by California Cancer Research Program Grants 99-00527V-10182 and 99-00524V-10258; S.A.I. was also supported by NIH grant CA84979. The Flint Men's Health Study was supported by the University of Michigan SPORE in Prostate Cancer (CA69568), the University of Michigan Department of Urology and the University of Michigan Comprehensive Cancer Center. K.A.C. was supported by grants CA69568 and CA79596, and I.O.G. and A.S.W. were supported by CA67044. D.A. is a Charles E. Culpeper Scholar of the Rockefeller Brothers Fund and a Burroughs Wellcome Fund Clinical Scholar in Translational Research. D.R. is supported by a Burroughs-Wellcome Career Development Award in the Biomedical Sciences.

Author information

Competing interests

The authors declare no competing financial interests.

Correspondence to David Reich.

Supplementary information

  1. Supplementary Fig. 1

    Proportion of genetic variation in HapMap samples captured by genotyping at 8q24. (PDF 56 kb)

  2. Supplementary Fig. 2

    Linkage disequilibrium scans across 8q24 for each of five populations. (PDF 477 kb)

  3. Supplementary Fig. 3

    Outlier removal and ancestry estimates. (PDF 114 kb)

  4. Supplementary Table 1

    Whole-genome admixture scan. (XLS 618 kb)

  5. Supplementary Table 2

    Linkage disequilibrium scan in five populations across the admixture peak. (XLS 2069 kb)

  6. Supplementary Table 3

    Phenotype and genotype data for each sample. (XLS 5846 kb)

  7. Supplementary Table 4

    Genotype data for 547 newly characterized polymorphisms in HapMap samples. (XLS 872 kb)

  8. Supplementary Table 5

    Linkage disequilibrium patterns among key polymorphisms in regions 1–3. (PDF 60 kb)

  9. Supplementary Table 6

    Recalculation of Table 2 for prospectively collected multiethnic cohort samples. (PDF 22 kb)

  10. Supplementary Table 7

    No evidence for epistatic interactions or nonmultiplicative effects among polymorphisms. (PDF 22 kb)

  11. Supplementary Table 8

    Association of variants to specific phenotypes of prostate cancer. (PDF 69 kb)

  12. Supplementary Table 9

    Polymorphisms used for outlier removal and ancestry estimates. (XLS 44 kb)

  13. Supplementary Methods (PDF 78 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading

Figure 1: Results of fine-mapping across the admixture peak, spanning the region 125.6–129.4 Mb defined in ref. 1.
Figure 2: Case-control association statistics by logistic regression for the 186 alleles for which we collected data in all five populations and are in the region 128.1–128.7 Mb.
Figure 3: The distributions of relative risks for prostate cancer in each of the populations, compared with the baseline relative risk (relative risk = 1) for individuals who do not carry any of the risk alleles at the seven markers we identified.