Title Genome-wide association study in east Asians identifies novelsusceptibility loci for breast cancer

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-b activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8610 in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85–0.94) and 0.80 (0.75–0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9610 from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6610), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively. Citation: Long J, Cai Q, Sung H, Shi J, Zhang B, et al. (2012) Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer. PLoS Genet 8(2): e1002532. doi:10.1371/journal.pgen. 1002532 Editor: Mark I. McCarthy, University of Oxford, United Kingdom Received July 21, 2011; Accepted December 23, 2011; Published February 23, 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This research was supported in part by U.S. National Institutes of Health grants R01CA124558, R01CA148667, R01CA64277, and R37CA070867, as well as Ingram Professorship and Research Reward funds to W Zheng; R01CA118229, R01CA092585, and Department of Defense (DOD) Idea Award BC011118 to X-O Shu; R01CA122756 and DOD Idea Award BC050791 to Q Cai; R01 CA137013 to J Long. Sample preparation and genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by Vanderbilt-Ingram Cancer Center (P30 CA68485). The SeBCS was supported by BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0001564). The KOHBRA/KOGES was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (#1020350). Participating studies (Principal Investigator, grant support) in the consortium are as PLoS Genetics | www.plosgenetics. org 1 February 2012 | Volume 8 | Issue 2 | e1002532 follows: the Shanghai Breast Cancer Study (W Zheng, R01CA64277), the Shanghai Women’s Health Study (W Zheng, R37CA070867), the Shanghai Breast Cancer Survival Study (X-O Shu, R01CA118229), the Shanghai Endometrial Cancer Study (X-O Shu, R01CA092585, contributing only controls to the consortium), the Seoul Breast Cancer Study (D-H Kang, the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea, 0620410-1), the Nanjing Study (H Shen, 09KJA330001, Jiangsu, China), the Tianjin Study (K Chen, the National Natural Science Foundation of China Grant No. 30771844), the Taiwan Biobank Study (C-Y Shen, DOH97-01), the Hong Kong Study (US Khoo, Research Grant Council, Hong Kong SAR, China, HKU 7520/05M and 76730M), the Guangzhou Breast Cancer Study (Z Ren, the National Natural Science Foundation of China Grant No. 81072383), the Multiethnic Cohort Study (BE Henderson, CA63464; LN Kolonel, CA54281; and CA Haiman, CA132839), the Nagano Breast Cancer Study (S Tsugane, Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049, and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan), and the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (K Tajima, Grants-in-Aid for Scientific Research on Priority Areas, 17015052, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; H Tanaka, Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare of Japan, H20-002). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: wei.zheng@vanderbilt.edu . These authors contributed equally to this work.