A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences

Thomas J. Hoffmann, Stephen K. Van Den Eeden, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Rebecca E. Graff, Michael N. Passarelli, Clinton L. Cario, Nima C. Emami, Chun R. Chao, Nirupa R. Ghai, Jun Shan, Dilrini K. Ranatunga, Charles P. Quesenberry, David Aaronson, Joseph Presti, Zhaoming Wang, Sonja I. Berndt, Stephen J. Chanock, Shannon K. McDonnellAmy J. French, Daniel J. Schaid, Stephen N. Thibodeau, Qiyuan Li, Matthew L. Freedman, Kathryn L. Penney, Lorelei A. Mucci, Christopher A. Haiman, Brian E. Henderson, Daniela Seminara, Mark N. Kvale, Pui Yan Kwok, Catherine Schaefer, Neil Risch, John S. Witte

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13 ; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). SIGNIFICANCE: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our fi ndings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. SIGNIFICANCE: Taken together, our fi ndings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our fi ndings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.

Original languageEnglish (US)
Pages (from-to)878-891
Number of pages14
JournalCancer discovery
Volume5
Issue number8
DOIs
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Oncology

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    Hoffmann, T. J., Van Den Eeden, S. K., Sakoda, L. C., Jorgenson, E., Habel, L. A., Graff, R. E., Passarelli, M. N., Cario, C. L., Emami, N. C., Chao, C. R., Ghai, N. R., Shan, J., Ranatunga, D. K., Quesenberry, C. P., Aaronson, D., Presti, J., Wang, Z., Berndt, S. I., Chanock, S. J., ... Witte, J. S. (2015). A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer discovery, 5(8), 878-891. https://doi.org/10.1158/2159-8290.CD-15-0315