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

Stacey, Simon N.; Sulem, Patrick; Zanon, Carlo; Gudjonsson, Sigurjon A.; Thorleifsson, Gudmar; Helgason, Agnar; Jonasdottir, Aslaug; Besenbacher, Soren; Kostic, Jelena P. and Fackenthal, James D., et al. (2010) In PLoS Genetics 6(7).
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).... (More)
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. (Less)
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PLoS Genetics
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6
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7
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Public Library of Science
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  • wos:000280512700025
  • scopus:77957343700
ISSN
1553-7404
DOI
10.1371/journal.pgen.1001029
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English
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db2fe302-8311-496f-a632-5baaca4e9ce4 (old id 1677328)
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2010-09-21 11:29:58
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@article{db2fe302-8311-496f-a632-5baaca4e9ce4,
  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.},
  author       = {Stacey, Simon N. and Sulem, Patrick and Zanon, Carlo and Gudjonsson, Sigurjon A. and Thorleifsson, Gudmar and Helgason, Agnar and Jonasdottir, Aslaug and Besenbacher, Soren and Kostic, Jelena P. and Fackenthal, James D. and Huo, Dezheng and Adebamowo, Clement and Ogundiran, Temidayo and Olson, Janet E. and Fredericksen, Zachary S. and Wang, Xianshu and Look, Maxime P. and Sieuwerts, Anieta M. and Martens, John W. M. and Pajares, Isabel and Garcia-Prats, Maria D. and Ramon-Cajal, Jose M. and de Juan, Ana and Panadero, Angeles and Ortega, Eugenia and Aben, Katja K. H. and Vermeulen, Sita H. and Asadzadeh, Fatemeh and van Engelenburg, K. C. Anton and Margolin, Sara and Shen, Chen-Yang and Wu, Pei-Ei and Försti, Asta and Lenner, Per and Henriksson, Roger and Johansson, Robert and Enquist, Kerstin and Hallmans, Goran and Jonsson, Thorvaldur and Sigurdsson, Helgi and Alexiusdottir, Kristin and Gudmundsson, Julius and Sigurdsson, Asgeir and Frigge, Michael L. and Gudmundsson, Larus and Kristjansson, Kristleifur and Halldorsson, Bjarni V. and Styrkarsdottir, Unnur and Gulcher, Jeffrey R. and Hemminki, Kari and Lindblom, Annika and Kiemeney, Lambertus A. and Mayordomo, Jose I. and Foekens, John A. and Couch, Fergus J. and Olopade, Olufunmilayo I. and Gudbjartsson, Daniel F. and Thorsteinsdottir, Unnur and Rafnar, Thorunn and Johannsson, Oskar T. and Stefansson, Kari},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1001029},
  volume       = {6},
  year         = {2010},
}