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

Zheng Y, Ogundiran TO, Falusi AG, Nathanson KL, John EM, Hennis AJ, Ambs S, Domchek SM, Rebbeck TR, Simon MS, Nemesure B, Wu SY, Leske MC, Odetunde A, Niu Q, Zhang J, Afolabi C, Gamazon ER, Cox NJ, Olopade CO, Olopade OI, Huo D
Carcinogenesis. 2013 34 (7): 1520-8

PMID: 23475944 · PMCID: PMC3697898 · DOI:10.1093/carcin/bgt090

Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified 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 signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.

MeSH Terms (18)

Adult African Continental Ancestry Group Alleles Biomarkers, Tumor Breast Neoplasms Case-Control Studies Chromosome Mapping Chromosomes, Human, Pair 6 Chromosomes, Human, Pair 16 Confidence Intervals Female Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study Humans Middle Aged Odds Ratio Polymorphism, Single Nucleotide

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