Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
oleh: Simon N Stacey, Patrick Sulem, Carlo Zanon, Sigurjon A Gudjonsson, Gudmar Thorleifsson, Agnar Helgason, Aslaug Jonasdottir, Soren Besenbacher, Jelena P Kostic, James D Fackenthal, Dezheng Huo, Clement Adebamowo, Temidayo Ogundiran, Janet E Olson, Zachary S Fredericksen, Xianshu Wang, Maxime P Look, Anieta M Sieuwerts, John W M Martens, Isabel Pajares, Maria D Garcia-Prats, Jose M Ramon-Cajal, Ana de Juan, Angeles Panadero, Eugenia Ortega, Katja K H Aben, Sita H Vermeulen, Fatemeh Asadzadeh, K C Anton van Engelenburg, Sara Margolin, Chen-Yang Shen, Pei-Ei Wu, Asta Försti, Per Lenner, Roger Henriksson, Robert Johansson, Kerstin Enquist, Göran Hallmans, Thorvaldur Jonsson, Helgi Sigurdsson, Kristin Alexiusdottir, Julius Gudmundsson, Asgeir Sigurdsson, Michael L Frigge, Larus Gudmundsson, Kristleifur Kristjansson, Bjarni V Halldorsson, Unnur Styrkarsdottir, Jeffrey R Gulcher, Kari Hemminki, Annika Lindblom, Lambertus A Kiemeney, Jose I Mayordomo, John A Foekens, Fergus J Couch, Olufunmilayo I Olopade, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Thorunn Rafnar, Oskar T Johannsson, Kari Stefansson
| Format: | Article |
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| Diterbitkan: | Public Library of Science (PLoS) 2010-07-01 |
Deskripsi
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.