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Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Genetics, QIMR (Queensland Institute for Medical Research) Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Nat Genet. 2015 Apr;47(4):373-80. doi: 10.1038/ng.3242. Epub 2015 Mar 9.
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
全基因组关联研究（GWAS）以及大规模重复研究已经在79个与乳腺癌相关的基因座中确定了常见变异，这些变异解释了该疾病约14%的家族性风险。为了确定新的易感基因座，我们对11项GWAS进行了荟萃分析，这些研究包括15748例乳腺癌病例和18084例对照，以及来自41项研究的46785例病例和42892例对照，这些研究在一个包含211155个标记的定制芯片（iCOGS）上进行基因分型。分析仅限于欧洲血统的女性。我们使用千人基因组计划参考面板通过插补生成了超过1100万个单核苷酸多态性（SNP）的基因型，并确定了15个与乳腺癌相关的新基因座，其P值小于5×10^(-8)。将关联分析与乳腺细胞系中的染色质免疫沉淀测序（ChIP-seq）染色质结合数据以及来自ENCODE的染色质相互作用分析技术（ChIA-PET）染色质相互作用数据相结合，我们在两个区域确定了可能的靶基因：18q12.3处的SETBP1以及1q2处的RNF115和PDZK1。一种关联似乎是由EXO1中编码的一个氨基酸替换所驱动。
