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dc.contributor.authorStacey, Simon N
dc.contributor.authorSulem, Patrick
dc.contributor.authorZanon, Carlo
dc.contributor.authorGudjonsson, Sigurjon A
dc.contributor.authorThorleifsson, Gudmar
dc.contributor.authorHelgason, Agnar
dc.contributor.authorJonasdottir, Aslaug
dc.contributor.authorBesenbacher, Soren
dc.contributor.authorKostic, Jelena P
dc.contributor.authorFackenthal, James D
dc.contributor.authorHuo, Dezheng
dc.contributor.authorAdebamowo, Clement
dc.contributor.authorOgundiran, Temidayo
dc.contributor.authorOlson, Janet E
dc.contributor.authorFredericksen, Zachary S
dc.contributor.authorWang, Xianshu
dc.contributor.authorLook, Maxime P
dc.contributor.authorSieuwerts, Anieta M
dc.contributor.authorMartens, John W M
dc.contributor.authorPajares, Isabel
dc.contributor.authorGarcia-Prats, Maria D
dc.contributor.authorRamon-Cajal, Jose M
dc.contributor.authorde Juan, Ana
dc.contributor.authorPanadero, Angeles
dc.contributor.authorOrtega, Eugenia
dc.contributor.authorAben, Katja K H
dc.contributor.authorVermeulen, Sita H
dc.contributor.authorAsadzadeh, Fatemeh
dc.contributor.authorvan Engelenburg, K C Anton
dc.contributor.authorMargolin, Sara
dc.contributor.authorShen, Chen-Yang
dc.contributor.authorWu, Pei-Ei
dc.contributor.authorFörsti, Asta
dc.contributor.authorLenner, Per
dc.contributor.authorHenriksson, Roger
dc.contributor.authorJohansson, Robert
dc.contributor.authorEnquist, Kerstin
dc.contributor.authorHallmans, Göran
dc.contributor.authorJonsson, Thorvaldur
dc.contributor.authorSigurdsson, Helgi
dc.contributor.authorAlexiusdottir, Kristin
dc.contributor.authorGudmundsson, Julius
dc.contributor.authorSigurdsson, Asgeir
dc.contributor.authorFrigge, Michael L
dc.contributor.authorGudmundsson, Larus
dc.contributor.authorKristjansson, Kristleifur
dc.contributor.authorHalldorsson, Bjarni V
dc.contributor.authorStyrkarsdottir, Unnur
dc.contributor.authorGulcher, Jeffrey R
dc.contributor.authorHemminki, Kari
dc.contributor.authorLindblom, Annika
dc.contributor.authorKiemeney, Lambertus A
dc.contributor.authorMayordomo, Jose I
dc.contributor.authorFoekens, John A
dc.contributor.authorCouch, Fergus J
dc.contributor.authorOlopade, Olufunmilayo I
dc.contributor.authorGudbjartsson, Daniel F
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorRafnar, Thorunn
dc.contributor.authorJohannsson, Oskar T
dc.contributor.authorStefansson, Kari
dc.date.accessioned2011-04-27T11:50:29Zen
dc.date.available2011-04-27T11:50:29Zen
dc.date.issued2010-07en
dc.date.submitted2011-04-27en
dc.identifier.citationPLoS Genet. 2010, 6(7):e1001029en
dc.identifier.issn1553-7404en
dc.identifier.pmid20661439en
dc.identifier.doi10.1371/journal.pgen.1001029en
dc.identifier.urihttp://hdl.handle.net/2336/128771en
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractWe 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.
dc.description.sponsorshipinfo:eu-repo/grantAgreement/EC/FP7/218071en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/218071en
dc.relation.urlhttp://dx.doi.org/10.1371/journal.pgen.1001029en
dc.subject.meshBreast Neoplasmsen
dc.subject.meshChromosomes, Human, Pair 6en
dc.subject.meshContinental Population Groupsen
dc.subject.meshEstrogen Receptor alphaen
dc.subject.meshFemaleen
dc.subject.meshGenetic Locien
dc.subject.meshGenetic Predisposition to Diseaseen
dc.subject.meshGenome-Wide Association Studyen
dc.subject.meshHumansen
dc.subject.meshPolymorphism, Single Nucleotideen
dc.titleAncestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.en
dc.typeArticleen
dc.contributor.departmentdeCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.isen
dc.identifier.journalPLoS geneticsen
refterms.dateFOA2018-09-12T11:13:17Z
html.description.abstractWe 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.


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