Identification of two novel mammographic density loci at 6Q25.1

Abstract

IntroductionMammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci.MethodsParticipants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account.ResultsGenome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10−8 for percent MD and P = 8.7 × 10−9 for absolute MD) and AREG (rs10034692, P = 6.7 × 10−9 for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10−9 for percent MD and P = 2.5 × 10−8 for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10−8 for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response.ConclusionsWe identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0591-2) contains supplementary material, which is available to authorized users.

Variants in 6q25.1 Are Associated with Mammographic Density in Malaysian Chinese Women

“…Notably, the associations for both rs7289126 with percent density and dense area and rs7816345 with percent density could not be replicated in a recent large-scale genetic association study including about 88,400 Swedish women (26). The SNP rs4849887 in INHBB was the only SNP included in our study that was reported to be associated with nondense area at genome-wide significance level previously (10,26). We observed a similar association with nondense area in the Chinese women.…”

“…In our study however, we observed that the effects of these alleles were in the opposite direction from those reported previously, although neither of these were statistically significant. Notably, the associations for both rs7289126 with percent density and dense area and rs7816345 with percent density could not be replicated in a recent large-scale genetic association study including about 88,400 Swedish women (26). The SNP rs4849887 in INHBB was the only SNP included in our study that was reported to be associated with nondense area at genome-wide significance level previously (10,26).…”

“…A two-stage fine mapping study of the 6q25 region in the Chinese population (28) revealed that rs10484919 is a candidate SNP for breast cancer risk where the risk allele is more common in Asian (35.4% in HapMap CHB) compared with European women (5.8% in HapMap CEU). The rs2046210 SNP is in strong linkage disequilibrium with rs60705924 (r 2 ¼ 0.93, 1000 Genomes Asian populations), a variant in CCDC170/ESR1 that was identified to be associated with volumetric and area-based mammographic density in Swedish women (26), but this was not evaluated in our study. Brand and colleagues (26) also reported a genome-wide significant association with density for another SNP, rs9485370, in the 6q25.1 locus mapping to the TAB2 gene.…”

Breast cancer risk prediction using a clinical risk model and polygenic risk score

“…Breast density is 60-70% heritable, and GWAS have identified 7 loci associated with percent dense area [37]. Our PRS includes at least two SNPs associated with density, rs10995190 (ZNF365) and rs3817198 (LSP1) and SNPs from ESR1, a locus that is associated with density [37,38]. Thus, our version of the PRS accounts for a small portion of the heritability of breast density, and inclusion of the PRS minimally affects the association between breast density and breast cancer.…”

Identification of Novel Common Breast Cancer Risk Variants in Latinas at the 6q25 Locus

“…Several GWAS studies have identified SNPs at 6q25 that are associated with breast cancer risk [13,18,20,[23][24][25][26][27] and mammographic density [23,[27][28][29][30]. The initial report identified a SNP in the intergenic region between ESR1 and CDCC170 in an East Asian population [24].…”