A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences.
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
- Division of Research, Kaiser Permanente, Northern California, Oakland, California. Department of Urology, University of California, San Francisco, San Francisco, California. wittej@humgen.ucsf.edu Stephen.Vandeneeden@kp.org.
- Division of Research, Kaiser Permanente, Northern California, Oakland, California.
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
- Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena, California.
- Department of Urology, Kaiser Oakland Medical Center, Northern California, Oakland, California.
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland.
- Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
- Medical College, Xiamen University, Xiamen, China.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts. The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
- National Cancer Institute, NIH, Bethesda, Maryland.
- Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California. Division of Research, Kaiser Permanente, Northern California, Oakland, California.
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California. Department of Urology, University of California, San Francisco, San Francisco, California. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. wittej@humgen.ucsf.edu Stephen.Vandeneeden@kp.org.
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 findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.