Estrogen interactions with breast cancer risk variants in regulatory DNA.

Insight into population-level gene-environment (GxE) interactions is a major goal in understanding polygenic diseases, such as breast cancer. We integrated massively parallel reporter assays (MPRA), chromatin profiling, and network analysis to identify estrogen-responsive breast cancer variants. Screening 1,604 GWAS-identified breast cancer variants identified 73 estrogen-modulated SNVs (emSNVs). Chromatin accessibility modeling validated allele-specific effects, identifying variants that disrupt pioneer factor binding to chromatin and others that modulate transcription factor (TF) recruitment to pre-accessible enhancers. emSNV targets converged on pathways including mitochondrial metabolism, NF-κB signaling, and chromatin regulation. Aggregating emSNVs into a polygenic risk score (PRS E2 ) revealed interactions with reproductive risk factors in 13,026 post-menopausal BRCA cases and 108,265 controls, including age at first birth (p=0.0052); a control PRS lacking estrogen-responsive variants showed no interactions. This framework bridges molecular and epidemiological GxE studies to uncover variants whose disease associations depend on environmental context, with implications for understanding polygenic disease risk.