TY - JOUR
T1 - Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer
AU - Chung, Charles C.
AU - Ciampa, Julia
AU - Yeager, Meredith
AU - Jacobs, Kevin B.
AU - Berndt, Sonja I.
AU - Hayes, Richard B.
AU - Gonzalez-Bosquet, Jesus
AU - Kraft, Peter
AU - Wacholder, Sholom
AU - Orr, Nick
AU - Yu, Kai
AU - Hutchinson, Amy
AU - Boland, Joseph
AU - Chen, Quan
AU - Feigelson, Heather Spencer
AU - Thun, Michael J.
AU - Diver, W. Ryan
AU - Albanes, Demetrius
AU - Virtamo, Jarmo
AU - Weinstein, Stephanie
AU - Schumacher, Fredrick R.
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Valeri, Antoine
AU - Andriole, Gerald L.
AU - Crawford, E. David
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Kolonel, Laurence
AU - Le Marchand, Loic
AU - Siddiq, Afshan
AU - Riboli, Elio
AU - Key, Tim J.
AU - Kaaks, Rudolf
AU - Isaacs, William B.
AU - Isaacs, Sarah D.
AU - Grönberg, Henrik
AU - Wiklund, Fredrik
AU - Xu, Jianfeng
AU - Vatten, Lars J.
AU - Hveem, Kristian
AU - Njolstad, Inger
AU - Gerhard, Daniela S.
AU - Tucker, Margaret
AU - Hoover, Robert N.
AU - Fraumeni, Joseph F.
AU - Hunter, David J.
AU - Thomas, Gilles
AU - Chatterjee, Nilanjan
AU - Chanock, Stephen J.
N1 - Funding Information:
This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH). The project was partially funded in part using grant CA129684 to J.X. and Contract Number HHSN261200800001E.
PY - 2011/7
Y1 - 2011/7
N2 - Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P < 10-8) with rs10896449 the most significant (P = 7.94 × 10-19). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P = 4.76 × 10-5, adjusted P = 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r2= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P = 5.92 × 10-3, adjusted P = 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r2= 0.17; r2=10896449-rs10896438, r2= 0.10; rs12793759- rs10896438, r2= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ~123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n = 31), rs10896438 (n = 24) and rs12793759 (n = 8). Our results indicate that a complex architec- ture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
AB - Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P < 10-8) with rs10896449 the most significant (P = 7.94 × 10-19). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P = 4.76 × 10-5, adjusted P = 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r2= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P = 5.92 × 10-3, adjusted P = 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r2= 0.17; r2=10896449-rs10896438, r2= 0.10; rs12793759- rs10896438, r2= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ~123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n = 31), rs10896438 (n = 24) and rs12793759 (n = 8). Our results indicate that a complex architec- ture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
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U2 - 10.1093/hmg/ddr189
DO - 10.1093/hmg/ddr189
M3 - Article
C2 - 21531787
AN - SCOPUS:79959841849
SN - 0964-6906
VL - 20
SP - 2869
EP - 2878
JO - Human molecular genetics
JF - Human molecular genetics
IS - 14
M1 - ddr189
ER -