Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers

Numerous single nucleotide polymorphisms (SNPs) associated withbreast cancer susceptibility have been identified by genome-wideassociation studies (GWAS). However, these SNPs were primarilydiscovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneousamong racial/ethnic populations, we evaluated commongenetic variants at 22 GWAS-identified breast cancer susceptibilityloci in a pooled sample of 1502 breast cancer cases and 1378 controlsof African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer riskvariants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry wereidentified in regions including 5p12 (odds ratio [OR] = 1.40, 95%confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22,95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95%CI = 1.08-1.38; P = 0.0015). We also found positive association signalsin three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previouslyconfirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers inthis study, compared with 22 GWAS-identified SNPs, could betterpredict breast cancer risk in women of African ancestry (per-alleleOR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10^-16). Our results demonstratethat fine mapping is a powerful approach to better characterizethe breast cancer risk alleles in diverse populations. Futurestudies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility withclinical implications throughout the African diaspora.