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- Title
Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
- Authors
Stacey, Simon N; Sulem, Patrick; Zanon, Carlo; Gudjonsson, Sigurjon A; Thorleifsson, Gudmar; Helgason, Agnar; Jonasdottir, Aslaug; Besenbacher, Soren; Kostic, Jelena P; Fackenthal, James D; Huo, Dezheng; Adebamowo, Clement; Ogundiran, Temidayo; Olson, Janet E; Fredericksen, Zachary S; Wang, Xianshu; Look, Maxime P; Sieuwerts, Anieta M; Martens, John W M; Pajares, Isabel; Garcia-Prats, Maria D; Ramon-Cajal, Jose M; de Juan, Ana; Panadero, Angeles; Ortega, Eugenia; Aben, Katja K H; Vermeulen, Sita H; Asadzadeh, Fatemeh; van Engelenburg, K C Anton; Margolin, Sara; Shen, Chen-Yang; Wu, Pei-Ei; Försti, Asta; Lenner, Per; Henriksson, Roger; Johansson, Robert; Enquist, Kerstin; Hallmans, Göran; Jonsson, Thorvaldur; Sigurdsson, Helgi; Alexiusdottir, Kristin; Gudmundsson, Julius; Sigurdsson, Asgeir; Frigge, Michael L; Gudmundsson, Larus; Kristjansson, Kristleifur; Halldorsson, Bjarni V; Styrkarsdottir, Unnur; Gulcher, Jeffrey R; Hemminki, Kari; Lindblom, Annika; Kiemeney, Lambertus A; Mayordomo, Jose I; Foekens, John A; Couch, Fergus J; Olopade, Olufunmilayo I; Gudbjartsson, Daniel F; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Johannsson, Oskar T; Stefansson, Kari
- 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.
- Publication
PLoS genetics, 2010, Vol 6, Issue 7, pe1001029
- ISSN
1553-7404
- Publication type
Journal Article
- DOI
10.1371/journal.pgen.1001029