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

Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G, Helgason A, Jonasdottir A, Besenbacher S, Kostic JP, Fackenthal JD, Huo D, Adebamowo C, Ogundiran T, Olson JE, Fredericksen ZS, Wang X, Look MP, Sieuwerts AM, Martens JW, Pajares I, Garcia-Prats MD, Ramon-Cajal JM, de Juan A, Panadero A, Ortega E, Aben KK, Vermeulen SH, Asadzadeh F, van Engelenburg KC, Margolin S, Shen CY, Wu PE, Försti A, Lenner P, Henriksson R, Johansson R, Enquist K, Hallmans G, Jonsson T, Sigurdsson H, Alexiusdottir K, Gudmundsson J, Sigurdsson A, Frigge ML, Gudmundsson L, Kristjansson K, Halldorsson BV, Styrkarsdottir U, Gulcher JR, Hemminki K, Lindblom A, Kiemeney LA, Mayordomo JI, Foekens JA, Couch FJ, Olopade OI, Gudbjartsson DF, Thorsteinsdottir U, Rafnar T, Johannsson OT, Stefansson K - PLoS Genet. (2010)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: deCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.is

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.

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Dendrograms showing r2 relationships between C6orf97-ESR1 SNPs in Europeans (CEU) and Yoruba Africans (YRI).On the left are listed the 37 SNPs that are correlated with an r2≥0.65 with rs2046210 (arrowed) in HapMap Han Chinese (CHB). In panel (a) the SNPs are arranged in a hierarchical cluster dendrogram based on the r2 values between them in the HapMap CEU sample of a European ancestry population. SNPs that were selected for genotyping are highlighted. SNPs indicated by *** are present on the Illumina Human Hap300 or HumanCNV370 chips used in the Icelandic GWAS. Panel (b) shows the same SNPs in a dendrogram based on r2 values from Yoruba Africans (HapMap YRI). Data are derived from HapMap Phase II release 23a.
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pgen-1001029-g002: Dendrograms showing r2 relationships between C6orf97-ESR1 SNPs in Europeans (CEU) and Yoruba Africans (YRI).On the left are listed the 37 SNPs that are correlated with an r2≥0.65 with rs2046210 (arrowed) in HapMap Han Chinese (CHB). In panel (a) the SNPs are arranged in a hierarchical cluster dendrogram based on the r2 values between them in the HapMap CEU sample of a European ancestry population. SNPs that were selected for genotyping are highlighted. SNPs indicated by *** are present on the Illumina Human Hap300 or HumanCNV370 chips used in the Icelandic GWAS. Panel (b) shows the same SNPs in a dendrogram based on r2 values from Yoruba Africans (HapMap YRI). Data are derived from HapMap Phase II release 23a.

Mentions: To search for SNPs that might detect the C6orf97-ESR1 signal in non-Asian ancestries, we first identified 36 SNPs that are well correlated (r2≥0.65) with rs2046210 in the Chinese, using the HapMap CHB dataset (Figure 1, lower panel, Figure S2). Then, using the HapMap CEU dataset, we observed the pattern of correlations between these SNPs in a population of European ancestry. The dendrogram in Figure 2A shows a hierarchical clustering of the 37 SNPs, based on their r2 values. We defined equivalence classes as sets of SNPs (or branches of the dendrogram) that show a correlation with an r2≥0.8 in CEU. We then selected a set of SNPs for genotyping such that at least one SNP in each equivalence class was included. These SNPs are highlighted in Figure 2A. We put in some redundant SNPs, partly to cover additional class fractionation in Africans (see below), and partly in order to examine two non-synonymous coding SNPs in the C6orof97 gene: V604I (rs6929137) and V683I (rs3734804). Single track Centaurus [18] assays were generated for the selected SNPs and validated by typing them in the HapMap CEU, CHB/JPT, and YRI samples.


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

Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G, Helgason A, Jonasdottir A, Besenbacher S, Kostic JP, Fackenthal JD, Huo D, Adebamowo C, Ogundiran T, Olson JE, Fredericksen ZS, Wang X, Look MP, Sieuwerts AM, Martens JW, Pajares I, Garcia-Prats MD, Ramon-Cajal JM, de Juan A, Panadero A, Ortega E, Aben KK, Vermeulen SH, Asadzadeh F, van Engelenburg KC, Margolin S, Shen CY, Wu PE, Försti A, Lenner P, Henriksson R, Johansson R, Enquist K, Hallmans G, Jonsson T, Sigurdsson H, Alexiusdottir K, Gudmundsson J, Sigurdsson A, Frigge ML, Gudmundsson L, Kristjansson K, Halldorsson BV, Styrkarsdottir U, Gulcher JR, Hemminki K, Lindblom A, Kiemeney LA, Mayordomo JI, Foekens JA, Couch FJ, Olopade OI, Gudbjartsson DF, Thorsteinsdottir U, Rafnar T, Johannsson OT, Stefansson K - PLoS Genet. (2010)

Dendrograms showing r2 relationships between C6orf97-ESR1 SNPs in Europeans (CEU) and Yoruba Africans (YRI).On the left are listed the 37 SNPs that are correlated with an r2≥0.65 with rs2046210 (arrowed) in HapMap Han Chinese (CHB). In panel (a) the SNPs are arranged in a hierarchical cluster dendrogram based on the r2 values between them in the HapMap CEU sample of a European ancestry population. SNPs that were selected for genotyping are highlighted. SNPs indicated by *** are present on the Illumina Human Hap300 or HumanCNV370 chips used in the Icelandic GWAS. Panel (b) shows the same SNPs in a dendrogram based on r2 values from Yoruba Africans (HapMap YRI). Data are derived from HapMap Phase II release 23a.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908678&req=5

pgen-1001029-g002: Dendrograms showing r2 relationships between C6orf97-ESR1 SNPs in Europeans (CEU) and Yoruba Africans (YRI).On the left are listed the 37 SNPs that are correlated with an r2≥0.65 with rs2046210 (arrowed) in HapMap Han Chinese (CHB). In panel (a) the SNPs are arranged in a hierarchical cluster dendrogram based on the r2 values between them in the HapMap CEU sample of a European ancestry population. SNPs that were selected for genotyping are highlighted. SNPs indicated by *** are present on the Illumina Human Hap300 or HumanCNV370 chips used in the Icelandic GWAS. Panel (b) shows the same SNPs in a dendrogram based on r2 values from Yoruba Africans (HapMap YRI). Data are derived from HapMap Phase II release 23a.
Mentions: To search for SNPs that might detect the C6orf97-ESR1 signal in non-Asian ancestries, we first identified 36 SNPs that are well correlated (r2≥0.65) with rs2046210 in the Chinese, using the HapMap CHB dataset (Figure 1, lower panel, Figure S2). Then, using the HapMap CEU dataset, we observed the pattern of correlations between these SNPs in a population of European ancestry. The dendrogram in Figure 2A shows a hierarchical clustering of the 37 SNPs, based on their r2 values. We defined equivalence classes as sets of SNPs (or branches of the dendrogram) that show a correlation with an r2≥0.8 in CEU. We then selected a set of SNPs for genotyping such that at least one SNP in each equivalence class was included. These SNPs are highlighted in Figure 2A. We put in some redundant SNPs, partly to cover additional class fractionation in Africans (see below), and partly in order to examine two non-synonymous coding SNPs in the C6orof97 gene: V604I (rs6929137) and V683I (rs3734804). Single track Centaurus [18] assays were generated for the selected SNPs and validated by typing them in the HapMap CEU, CHB/JPT, and YRI samples.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: deCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.is

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.

Show MeSH
Related in: MedlinePlus