Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia

Background. Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. Methods. We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). Results. In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10⁻⁶; rs12322371, OR = 1.14, p = 3.15×10⁻⁶), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10⁻⁶). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10⁻⁵; rs76959804, OR = 3.57, p = 1.77×10⁻⁵) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10⁻⁶). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). Conclusion. The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.