Evaluations of significant loci associated with mammographic breast density in Korean women

Mammographic density is a strong risk factor for breast cancer and comprises four quantitative phenotypes: breast area (BA), dense area (DA), non-dense area (NDA), and percent density (PD). Although genome-wide association studies (GWASs) have identified loci associated with mammographic density, most evidence has been derived from populations of European ancestry. Therefore, we aimed to assess genetic variants associated with breast density phenotypes in Korean women.

We conducted a GWAS of BA, DA, NDA, and PD phenotypes in 3,701 women. Association analyses were performed under additive, dominant, and recessive genetic models, and genome-wide significance was defined as P < 5 × 10^- 8. Loci significantly associated with each phenotype were identified using linear regression models after adjusting for age, body mass index, ancestry-informative principal components, and reproductive factors. Genome-wide significant variants from the additive-model GWAS were further investigated using Functional Mapping and Annotation to define genomic risk loci, annotate candidate variants, and map candidate genes.

In 3,701 women, the mean age at mammographic density assessment was 40.3 years. Mean BA, DA, NDA, and PD were 87.6 cm², 30.7 cm², 56.9 cm², and 37.9%, respectively. Three associated loci were identified at 6q25.1 (rs2046210), 8p11.23 (rs13365225), and 22q13.2 (rs78694459). For DA, two associated loci were identified at 6q25.1 (rs12665607) and 22q13.1 (rs17002034). For NDA, one associated locus was observed at 8p11.23 (rs13365225), and for PD, one associated locus was observed at 6q25.1 (rs12665607). The most consistent signal was observed at 6q25.1, which was associated with BA, DA, and PD phenotypes and mapped to CCDC170/ESR1. The 8p11.23 locus, mapped to KCNU1, was associated primarily with BA and NDA phenotypes, whereas the 22q13 locus, mapped to MKL1, was associated with BA and DA phenotypes. Functional annotation showed that most candidate variants were intronic or intergenic, with only a small number of exonic non-synonymous variants in CCDC170 and KCNU1. Stratified analysis by age also showed comparable results.

Our findings indicate that mammographic density phenotypes are influenced by a limited number of recurrent loci: 6q25.1, 8p11.23, and 22q13 in Korean women. All three loci identified in this study were previously associated with breast density and breast cancer, validating our findings and suggesting partial genetic overlap between mammographic density and breast cancer risk. Further research is warranted to clarify the genetic basis of breast density and its relationship with breast cancer risk in the Korean population, including larger studies and functional investigations of the implicated loci.