PLoS Genetics (Jul 2010)

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

  • 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

DOI
https://doi.org/10.1371/journal.pgen.1001029
Journal volume & issue
Vol. 6, no. 7
p. e1001029

Abstract

Read online

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.