title: A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hoffmann
authors.affiliation: 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.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Van Den Eeden
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Lori C
authors.initials: LC
authors.lastname: Sakoda
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Jorgenson
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Habel
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Graff
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Passarelli
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Clinton L
authors.initials: CL
authors.lastname: Cario
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Nima C
authors.initials: NC
authors.lastname: Emami
authors.affiliation: Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena, California.
authors.forename: Chun R
authors.initials: CR
authors.lastname: Chao
authors.affiliation: Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena, California.
authors.forename: Nirupa R
authors.initials: NR
authors.lastname: Ghai
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Shan
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Dilrini K
authors.initials: DK
authors.lastname: Ranatunga
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Quesenberry
authors.affiliation: Department of Urology, Kaiser Oakland Medical Center, Northern California, Oakland, California.
authors.forename: David
authors.initials: D
authors.lastname: Aaronson
authors.affiliation: Department of Urology, Kaiser Oakland Medical Center, Northern California, Oakland, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Presti
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.affiliation: Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Medical College, Xiamen University, Xiamen, China.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.affiliation: 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.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.affiliation: 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.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kvale
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: 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.
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
authors.affiliation: 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.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D012306:Risk
chemical_list: D014408:Biomarkers, Tumor