Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus

Abstract

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Figure 1. Overview of the C6orf97-ESR1 breast cancer susceptibility locus.

The upper panel shows a view of the genomic region of chromosome 6, nucleotides 151,930,000–152,200,000 taken from the UCSC browser Build 36 assembly (hg18). The C6orf97 gene and the four RefSeq isoforms of ESR1 are shown. Below them is a histogram of the local recombination rates calculated as previously described from HapMap phase II release 22 data. Below that is a track showing the locations of the SNPs that are correlated (r²≥0.65) with rs2046210 in Han Chinese (“Eq Class SNPs”). The lower panel shows a zoomed view of the region nucleotides 151,960,548–152,013,381, containing the Eq Class SNPs. RefSeq genes and recombination rates are as in the upper panel.

Figure 2. Dendrograms showing r² relationships between C6orf97-ESR1 SNPs in Europeans (CEU) and Yoruba Africans (YRI).

On the left are listed the 37 SNPs that are correlated with an r²≥0.65 with rs2046210 (arrowed) in HapMap Han Chinese (CHB). In panel (a) the SNPs are arranged in a hierarchical cluster dendrogram based on the r² values between them in the HapMap CEU sample of a European ancestry population. SNPs that were selected for genotyping are highlighted. SNPs indicated by *** are present on the Illumina Human Hap300 or HumanCNV370 chips used in the Icelandic GWAS. Panel (b) shows the same SNPs in a dendrogram based on r² values from Yoruba Africans (HapMap YRI). Data are derived from HapMap Phase II release 23a.