TY - JOUR
T1 - A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences
AU - Hoffmann, Thomas J.
AU - Van Den Eeden, Stephen K.
AU - Sakoda, Lori C.
AU - Jorgenson, Eric
AU - Habel, Laurel A.
AU - Graff, Rebecca E.
AU - Passarelli, Michael N.
AU - Cario, Clinton L.
AU - Emami, Nima C.
AU - Chao, Chun R.
AU - Ghai, Nirupa R.
AU - Shan, Jun
AU - Ranatunga, Dilrini K.
AU - Quesenberry, Charles P.
AU - Aaronson, David
AU - Presti, Joseph
AU - Wang, Zhaoming
AU - Berndt, Sonja I.
AU - Chanock, Stephen J.
AU - McDonnell, Shannon K.
AU - French, Amy J.
AU - Schaid, Daniel J.
AU - Thibodeau, Stephen N.
AU - Li, Qiyuan
AU - Freedman, Matthew L.
AU - Penney, Kathryn L.
AU - Mucci, Lorelei A.
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Seminara, Daniela
AU - Kvale, Mark N.
AU - Kwok, Pui Yan
AU - Schaefer, Catherine
AU - Risch, Neil
AU - Witte, John S.
N1 - Publisher Copyright:
©2015 American Association for Cancer Research
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84939182677
U2 - 10.1158/2159-8290.CD-15-0315
DO - 10.1158/2159-8290.CD-15-0315
M3 - Article
C2 - 26034056
AN - SCOPUS:84939182677
SN - 2159-8274
VL - 5
SP - 878
EP - 891
JO - Cancer Discovery
JF - Cancer Discovery
IS - 8
ER -