title: 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.
authors.affiliation: deCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.is
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mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha