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 α (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 = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 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.

Breast Cancer Susceptibility Variants and Mammographic Density Phenotypes in Norwegian Postmenopausal Women

“…Our findings with 6q25.1-rs3734805 and 6q25.1-rs9383938 are consistent with the GWAS study on breast cancer where these variants were first reported (28) and with a subsequent case-control study of 6q25.1 (55). A meta-analysis of five GWAS of MD within the Marker Of DEnsity (MODE) consortium, examined 23 of the established breast cancer variants with MD and reported a significant association of rs2046210 -ESR1 and MD (18).…”

A Genome-wide Breast Cancer Scan in African Americans

“…The inability to replicate associations with the index signals despite adequate statistical power (.70% power for 12 of 19 variants) suggests that they are unlikely to be functional variants or capture the functional variants as efficiently in this population. Our ability to find associated markers in five regions where index signals were not significantly associated with risk also demonstrates the value of testing common variation at GWAS-identified risk loci in additional populations (14,16,17,22,37,38).…”

“…We tested the 19 validated breast cancer risk variants (referred as "index variants") at 1p11, 2q35, 3p24, 5p12, 5q11, 6q25, 8q24, 9p21, 9q31, 10p15, 10q21, 10q22, 10q26, 11p15, 11q13, 14q24, 16q12, 17q23 and 19p13 in models adjusted for age, study, global ancestry (the first 10 eigenvectors) and local ancestry; 5,[12][13][14][15][16][17] 17 SNPs were directly genotyped, while 2 were imputed using MACH (r 2 >0.98). All 19 variants were common (≥0.05) in African Americans, with 11 variants being more common in Europeans than African Americans.…”

Validation of associations between ESR1 variants and breast cancer risk in Chinese cohorts

“…Recently, three genome-wide association studies (GWASs) have revealed that three single-nucleotide polymorphisms (SNPs; rs3757318, rs2046210, and rs3734805) near or in the ESR1 gene are associated with breast cancer (Zheng et al, 2009;Turnbull et al, 2010;Fletcher et al, 2011). However, the results of replication studies were not consistent owing to the sample sizes used and the diverse genetic backgrounds of the ethnic groups involved (Stacey et al, 2010;Zhong and Prentice, 2010;Campa et al, 2011).…”