A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

Gilles Thomas, Kevin B. Jacobs, Peter Kraft, Meredith Yeager, Sholom Wacholder, David G. Cox, Susan E. Hankinson, Amy Hutchinson, Zhaoming Wang, Kai Yu, Nilanjan Chatterjee, Montserrat Garcia-Closas, Jesus Gonzalez-Bosquet, Ludmila Prokunina-Olsson, Nick Orr, Walter C. Willett, Graham A. Colditz, Regina G. Ziegler, Christine D. Berg, Saundra S. BuysCatherine A. McCarty, Heather Spencer Feigelson, Eugenia E. Calle, Michael J. Thun, Ryan Diver, Ross Prentice, Rebecca Jackson, Charles Kooperberg, Rowan Chlebowski, Jolanta Lissowska, Beata Peplonska, Louise A. Brinton, Alice Sigurdson, Michele Doody, Parveen Bhatti, Bruce H. Alexander, Julie Buring, I. Min Lee, Lars J. Vatten, Kristian Hveem, Merethe Kumle, Richard B. Hayes, Margaret Tucker, Daniela S. Gerhard, Joseph F. Fraumeni, Robert N. Hoover, Stephen J. Chanock, David J. Hunter

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459 Scopus citations


We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 × 10-10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 × 10-7) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

Original languageEnglish
Pages (from-to)579-584
Number of pages6
JournalNature Genetics
Issue number5
StatePublished - May 2009


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