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

Author： Chung Charles C. Ciampa Julia Yeager Meredith Jacobs Kevin B Berndt Sonja I. Hayes Richard B. Gonzalez-Bosquet Jesus Kraft Peter Wacholder Sholom Orr Nick Yu Kai Hutchinson Amy Boland Joseph Chen Quan Feigelson Heather Spencer Thun Michael J. Diver W. Ryan Albanes Demetrius Virtamo Jarmo Weinstein Stephanie Schumacher Fredrick R. Cancel-Tassin Geraldine Cussenot Olivier Valeri Antoine Andriole Gerald L. Crawford E. David Haiman Christopher A. Henderson Brian E. Kolonel Laurence Le Marchand Loic Siddiq Afshan Riboli Elio Key Tim J. Kaaks Rudolf Isaacs William B. Isaacs Sarah D. Grönberg Henrik Wiklund Fredrik Xu Jianfeng Vatten Lars J. Hveem Kristian Njolstad Inger Gerhard Daniela S. Tucker Margaret Hoover Robert N. Fraumeni Joseph F. Hunter David J. Thomas Gilles Chatterjee Nilanjan Chanock Stephen J.

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.20, Iss.14, 2011-07, pp. : 2869-2878

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Abstract

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<>⁻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; rs10896449–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 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.