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


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 = 1.2 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.

SUBMITTER: Stacey SN 

PROVIDER: S-EPMC2908678 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

Stacey Simon N SN   Sulem Patrick P   Zanon Carlo C   Gudjonsson Sigurjon A SA   Thorleifsson Gudmar G   Helgason Agnar A   Jonasdottir Aslaug A   Besenbacher Soren S   Kostic Jelena P JP   Fackenthal James D JD   Huo Dezheng D   Adebamowo Clement C   Ogundiran Temidayo T   Olson Janet E JE   Fredericksen Zachary S ZS   Wang Xianshu X   Look Maxime P MP   Sieuwerts Anieta M AM   Martens John W M JW   Pajares Isabel I   Garcia-Prats Maria D MD   Ramon-Cajal Jose M JM   de Juan Ana A   Panadero Angeles A   Ortega Eugenia E   Aben Katja K H KK   Vermeulen Sita H SH   Asadzadeh Fatemeh F   van Engelenburg K C Anton KC   Margolin Sara S   Shen Chen-Yang CY   Wu Pei-Ei PE   Försti Asta A   Lenner Per P   Henriksson Roger R   Johansson Robert R   Enquist Kerstin K   Hallmans Göran G   Jonsson Thorvaldur T   Sigurdsson Helgi H   Alexiusdottir Kristin K   Gudmundsson Julius J   Sigurdsson Asgeir A   Frigge Michael L ML   Gudmundsson Larus L   Kristjansson Kristleifur K   Halldorsson Bjarni V BV   Styrkarsdottir Unnur U   Gulcher Jeffrey R JR   Hemminki Kari K   Lindblom Annika A   Kiemeney Lambertus A LA   Mayordomo Jose I JI   Foekens John A JA   Couch Fergus J FJ   Olopade Olufunmilayo I OI   Gudbjartsson Daniel F DF   Thorsteinsdottir Unnur U   Rafnar Thorunn T   Johannsson Oskar T OT   Stefansson Kari K  

PLoS genetics 20100722 7


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  ...[more]

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