Abstract
BackgroundMultiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.MethodWe performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.ResultsAnalysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.ConclusionThis study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.
Highlights
Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk
SNPs rs7297051, rs805510 and rs113824616 were associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants
Using forward stepwise selection, we identified two SNPs that were independently associated with breast cancer risk with conditional P < 0.0001, tagging two independent signals (Table 1, Fig. 1)
Summary
Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. A previous genome-wide association study (GWAS) identified a common single nucleotide polymorphism (SNP), rs10771399 (termed the index SNP in this paper) at 12p11 to be associated with breast cancer risk in women of European descent [1]. This association, which did not vary by estrogen receptor (ER) status, was one of the most significant associations found for breast cancer risk in Breast cancer 1 (BRCA1) mutation carriers so far, and the association was predominantly found in carriers with ERnegative (ER-(-)) breast cancer [2, 3]. In order to identify additional association signals at the12p11 locus with breast cancer risk, understand the underlying mechanisms and potential causal variants responsible for the association, we conducted a large fine-scale mapping study including data from 55,540 breast cancer cases and 51,168 controls in the Breast Cancer Association Consortium (BCAC) and 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
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