Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia
Creators: name: Stram, Daniel O
name: Cai, Qiuyin
name: The Ghana Breast Health Study Team
name: Guo, Xingyi
name: Ojengbede, Oladosu
name: Bolla, Manjeet K
name: Lunetta, Kathryn L
name: Olopade, Olufunmilayo I
name: Elston, Robert C
name: Dennis, Joe
name: Haddad, Stephen A
name: Ochs-Balcom, Heather M
name: Huo, Dezheng
name: Shu, Xiao-Ou
name: Troester, Melissa A
name: García-Closas, Montserrat
name: John, Esther M
name: Long, Jirong
name: O’Brien, Katie M
name: Olshan, Andrew F
name: Zheng, Wei
name: Ogundiran, Temidayo O
name: Hu, Jennifer J
name: Jia, Guochong
name: Deming, Sandra L
name: Bandera, Elisa V
name: Ruiz-Narváez, Edward A
name: Yao, Song
name: Li, Bingshan
name: Zirpoli, Gary
name: Haiman, Christopher
name: Nemesure, Barbara
name: Press, Michael F
name: Wang, Qin
name: Chanock, Stephen J
name: Mancuso, Nicholas
name: Sandler, Dale P
name: Sucheston-Campbell, Lara E
name: Ahearn, Thomas
name: Rodriguez-Gil, Jorge L
name: Ingles, Sue A
name: Preus, Leah
name: Pharoah, Paul D P
name: Weinberg, Clarice R
name: Easton, Douglas F
name: Hennis, Anselm
name: Taylor, Jack A
name: Nyante, Sarah
name: Teerlink, Craig C
name: Blot, William
name: Nathanson, Katherine L
name: Ambs, Stefan
name: Sanderson, Maureen
name: Ping, Jie
name: Conti, David V
name: Bensen, Jeannette T
name: Palmer, Julie
name: Michailidou, Kyriaki
name: Ambrosone, Christine B
name: Dunning, Alison M
name: Figueroa, Jonine
name: Ziegler, Regina G
name: Du, Zhaohui
name: Gao, Guimin
name: Kitahara, Cari M
name: Bernstein, Leslie
Publisher: name: Oxford University Press (OUP)
Year: 2024

description: 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.