A comprehensive examination of breast cancer risk loci in African American women

Abstract

Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

Figure 1.

Effect estimates of overall breast cancer risk for all 73 known risk variants in GWAS-discovery and African-ancestry populations. Red circles represent the per-allele ORs estimated in women of African ancestry (AA). Blue diamonds represent the per-allele ORs reported in the initial GWAS. The horizontal lines represent 95% confidence limits. Asterisks represent SNPs that were reported for ER− disease. For each tested allele, frequencies in GWAS-discovery and African-ancestry populations are provided in parentheses. SNPs are sorted based on their ORs in AA. Detailed information for each SNP is provided in Supplementary Material, Table S1.

Figure 2.

Regional plot of the secondary signal (rs17104923) on 14q13. The chromosomal position (based on GRCh37) of SNPs on 14q13 against –log₁₀ P-values for ER+ disease is shown. Genotyped SNPs are represented by circles. Imputed SNPs are represented by squares. The secondary signal rs17104923 is plotted by a purple square. The red arrow denotes the GWAS index variant rs2236007. SNPs surrounding the top SNPs are colored to indicate the LD structure using pairwise r² in reference to rs17104923 from the May 2012 AFR panel of 1000 Genomes. The plots were generated using LocusZoom (18).