Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus

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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 = 1.2x10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9x10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9x10(-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.

Details

Authors
  • 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
  • Per Lenner
  • Roger Henriksson
  • Robert Johansson
  • Kerstin Enquist
  • Goran 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
  • 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
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Public Health, Global Health, Social Medicine and Epidemiology
Original languageEnglish
JournalPLoS Genetics
Volume6
Issue number7
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes