TY - JOUR
T1 - Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus
AU - Stacey, Simon N.
AU - Sulem, Patrick
AU - Zanon, Carlo
AU - Gudjonsson, Sigurjon A.
AU - Thorleifsson, Gudmar
AU - Helgason, Agnar
AU - Jonasdottir, Aslaug
AU - Besenbacher, Soren
AU - Kostic, Jelena P.
AU - Fackenthal, James D.
AU - Huo, Dezheng
AU - Adebamowo, Clement
AU - Ogundiran, Temidayo
AU - Olson, Janet E.
AU - Fredericksen, Zachary S.
AU - Wang, Xianshu
AU - Look, Maxime P.
AU - Sieuwerts, Anieta M.
AU - Martens, John W.M.
AU - Pajares, Isabel
AU - Garcia-Prats, Maria D.
AU - Ramon-Cajal, Jose M.
AU - de Juan, Ana
AU - Panadero, Angeles
AU - Ortega, Eugenia
AU - Aben, Katja K.H.
AU - Vermeulen, Sita H.
AU - Asadzadeh, Fatemeh
AU - Anton van Engelenburg, K. C.
AU - Margolin, Sara
AU - Shen, Chen Yang
AU - Wu, Pei Ei
AU - Försti, Asta
AU - Lenner, Per
AU - Henriksson, Roger
AU - Johansson, Robert
AU - Enquist, Kerstin
AU - Hallmans, Göran
AU - Jonsson, Thorvaldur
AU - Sigurdsson, Helgi
AU - Alexiusdottir, Kristin
AU - Gudmundsson, Julius
AU - Sigurdsson, Asgeir
AU - Frigge, Michael L.
AU - Gudmundsson, Larus
AU - Kristjansson, Kristleifur
AU - Halldorsson, Bjarni V.
AU - Styrkarsdottir, Unnur
AU - Gulcher, Jeffrey R.
AU - Hemminki, Kari
AU - Lindblom, Annika
AU - Kiemeney, Lambertus A.
AU - Mayordomo, Jose I.
AU - Foekens, John A.
AU - Couch, Fergus J.
AU - Olopade, Olufunmilayo I.
AU - Gudbjartsson, Daniel F.
AU - Thorsteinsdottir, Unnur
AU - Rafnar, Thorunn
AU - Johannsson, Oskar T.
AU - Stefansson, Kari
PY - 2010/7
Y1 - 2010/7
N2 - 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 α (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 = 1.2×10-3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10-4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10-7), was without significant heterogeneity between ancestries (Phet = 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.
AB - 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 α (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 = 1.2×10-3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10-4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10-7), was without significant heterogeneity between ancestries (Phet = 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.
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U2 - 10.1371/journal.pgen.1001029
DO - 10.1371/journal.pgen.1001029
M3 - Article
C2 - 20661439
AN - SCOPUS:77957343700
SN - 1553-7390
VL - 6
SP - 1
EP - 12
JO - PLoS genetics
JF - PLoS genetics
IS - 7
ER -