From Association to Mechanism: Regulatory Annotation and Pathway Mapping of Genes Surrounding Breast Cancer Risk Variants

ABSTRACT Inherited factors account for a large share of breast cancer susceptibility, yet the biological consequences of most risk variants are still poorly understood. To address this gap, we studied 175 breast cancer risk variants confirmed by genome‐wide association studies and gathered the genes that lie near them. Two complementary gene sets were assembled. The first collected every gene immediately flanking each risk variant, regardless of distance. The second kept only the closest gene together with genes tagged by variants in strong linkage disequilibrium within a 100 kb interval. Across both sets, the clearest biological signal pointed to androgen receptor‐mediated signaling. Pathway mapping additionally implicated the Wnt/β‐catenin and Hedgehog cascades, and this pattern was most evident in the flanking‐gene set. With HaploReg, we annotated correlated variants at each locus and recovered features that mark active regulation. Enrichment testing returned a 4.8‐fold excess of DNase I hypersensitivity in a breast cancer cell line and a 15.7‐fold excess of enhancer motifs in a stem cell line. Together, these results indicate that breast cancer risk markers and their correlated variants influence the activity of neighboring genes and converge on a small number of signaling pathways central to mammary biology.