Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer

被引：35

作者：

Chung, Charles C. ^{[1
,2
]}

Ciampa, Julia ^{[2
]}

Yeager, Meredith ^{[2
,4
]}

Jacobs, Kevin B. ^{[2
,4
]}

Berndt, Sonja I. ^{[2
]}

Hayes, Richard B. ^{[2
,5
]}

Gonzalez-Bosquet, Jesus ^{[1
,2
]}

Kraft, Peter ^{[6
]}

Wacholder, Sholom ^{[2
]}

Orr, Nick ^{[2
]}

Yu, Kai ^{[2
]}

Hutchinson, Amy ^{[2
,4
]}

Boland, Joseph ^{[2
,4
]}

Chen, Quan ^{[2
,4
]}

Feigelson, Heather Spencer ^{[8
]}

Thun, Michael J. ^{[8
]}

Diver, W. Ryan ^{[8
]}

Albanes, Demetrius ^{[2
]}

Virtamo, Jarmo ^{[9
]}

Weinstein, Stephanie ^{[2
]}

Schumacher, Fredrick R. ^{[7
]}

Cancel-Tassin, Geraldine ^{[10
]}

Cussenot, Olivier ^{[10
]}

Valeri, Antoine ^{[10
]}

Andriole, Gerald L. ^{[11
]}

Crawford, E. David ^{[12
,13
]}

Haiman, Christopher A. ^{[14
]}

Henderson, Brian E. ^{[14
]}

Kolonel, Laurence ^{[15
]}

Le Marchand, Loic ^{[15
]}

Siddiq, Afshan ^{[16
]}

Riboli, Elio ^{[16
]}

Key, Tim J. ^{[17
]}

Kaaks, Rudolf ^{[18
]}

Isaacs, William B. ^{[19
]}

Isaacs, Sarah D. ^{[19
]}

Gronberg, Henrik ^{[20
]}

Wiklund, Fredrik ^{[20
]}

Xu, Jianfeng ^{[21
]}

Vatten, Lars J. ^{[22
]}

Hveem, Kristian ^{[22
]}

Njolstad, Inger ^{[23
]}

Gerhard, Daniela S. ^{[3
]}

Tucker, Margaret ^{[2
]}

Hoover, Robert N. ^{[2
]}

Fraumeni, Joseph F., Jr. ^{[2
]}

Hunter, David J. ^{[2
,7
,24
]}

Thomas, Gilles ^{[2
,25
]}

Chatterjee, Nilanjan ^{[2
]}

Chanock, Stephen J. ^{[1
,2
]}

机构：

[1] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Adv Technol Ctr NCI,Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA

[2] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA

[3] NCI, Off Canc Genom, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA

[4] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA

[5] NYU Sch Med, Dept Environm Med, New York, NY USA

[6] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[8] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA

[9] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[10] Hop Tenon, AP HP, Ctr Rech Pathol Prostat, F-75970 Paris, France

[11] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA

[12] Univ Colorado, Dept Surg, Denver, CO 80202 USA

[13] Univ Colorado, Hlth Sci Ctr, Denver, CO USA

[14] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[15] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA

[16] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England

[17] Univ Oxford, Canc Epidemiol Unit, Oxford, England

[18] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany

[19] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA

[20] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden

[21] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA

[22] Norwegian Univ Sci & Technol, Dept Publ Hlth, N-7034 Trondheim, Norway

[23] Univ Tromso, Inst Community Med, Tromso, Norway

[24] Harvard Univ, Brigham & Womens Hosp, Channing Lab, Sch Med, Boston, MA 02115 USA

[25] Univ Lyon 1, F-69365 Lyon, France

来源：

HUMAN MOLECULAR GENETICS | 2011年 / 20卷 / 14期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; RECOMBINATION HOTSPOTS; LINKAGE DISEQUILIBRIUM; GENETIC-VARIATION; COMMON VARIANT; BREAST-CANCER; IDENTIFIES; POPULATION; MYEOV;

D O I：

10.1093/hmg/ddr189

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 x 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P = 4.76 x 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 (r(2) = 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P = 5.92 x 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, r(2) = 0.17; rs10896449-rs10896438, r(2) = 0.10; rs12793759-rs10896438, r(2) = 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across similar to 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 architecture 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.

引用

页码：2869 / 2878

页数：10

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