Genetic and Cellular Architecture of Breast Cancer Risk Across Ancestries

Abstract

BackgroundBreast cancer genome-wide association studies (GWAS) have identified more than 200 susceptibility loci, but most studies are dominated by European and East Asian populations. MethodsWe analyzed breast cancer GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR), and Hispanic/Latina (H/L) samples (159,297 cases and 212,102 controls). We estimated logit-scale SNP-based heritability, polygenicity, and cross-ancestry genetic correlation, partitioned heritability across functional annotations, and integrated GWAS results with the Tabula Sapiens single-cell atlas using scDRS+. ResultsThe logit-scale heritability of breast cancer ranged from h2 =0.47 (SE = 0.07) in EAS to AFR h2 =0.61 (SE = 0.10), with no significant differences across ancestries (p=0.63). The model-implied number of non-null susceptibility SNPs in the sparse normal-mixture effect-size model also varied from 4,446 (SE = 3,100) in EAS to 8,308 (SE = 2,751) in AFR, but differences were not significant across ancestries (p=0.55). Cross-sample genetic correlations varied, with the strongest correlation between EUR and EAS ({rho} = 0.79, SE = 0.08) and weakest between AFR and H/L ({rho} = 0.26, SE = 0.24). Regulatory annotations were enriched for breast cancer heritability across samples. Integration with single-cell expression profiles implicated ancestry-shared associations with innate immune, secretory epithelial, and stromal cell types. ConclusionThese results indicate substantial cross-ancestry sharing of breast cancer polygenic architecture, highlight a consistent contribution of regulatory variation, and identify convergent cellular contexts that motivate functional follow-up and inform expectations for the transferability and attainable performance of common-variant risk prediction across populations.