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

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

doi:10.1371/journal.pgen.1001029

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

Simon N. Stacey, Patrick Sulem, Carlo Zanon, Sigurjon A. Gudjonsson, Gudmar Thorleifsson, Agnar Helgason, Aslaug Jonasdottir, Soren Besenbacher, Jelena P. Kostic, James D. Fackenthal, Dezheng Huo, Clement Adebamowo, Temidayo Ogundiran, Janet E. Olson, Zachary S. Fredericksen, Xianshu Wang, Maxime P. Look, Anieta M. Sieuwerts, John W. M. Martens, Isabel PajaresMaria D. Garcia-Prats, Jose M. Ramon-Cajal, Ana de Juan, Angeles Panadero, Eugenia Ortega, Katja K. H. Aben, Sita H. Vermeulen, Fatemeh Asadzadeh, K. C. Anton van Engelenburg, Sara Margolin, Chen-Yang Shen, Pei-Ei Wu, Asta Försti, Per Lenner, Roger Henriksson, Robert Johansson, Kerstin Enquist, Goran Hallmans, Thorvaldur Jonsson, Helgi Sigurdsson, Kristin Alexiusdottir, Julius Gudmundsson, Asgeir Sigurdsson, Michael L. Frigge, Larus Gudmundsson, Kristleifur Kristjansson, Bjarni V. Halldorsson, Unnur Styrkarsdottir, Jeffrey R. Gulcher, Kari Hemminki, Annika Lindblom, Lambertus A. Kiemeney, Jose I. Mayordomo, John A. Foekens, Fergus J. Couch, Olufunmilayo I. Olopade, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Thorunn Rafnar, Oskar T. Johannsson, Kari Stefansson

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	PLoS Genetics
Volume	6
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1001029
Publication status	Published - 2010

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Public Health, Global Health, Social Medicine and Epidemiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1001029

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Stacey, S. N., Sulem, P., Zanon, C., Gudjonsson, S. A., Thorleifsson, G., Helgason, A., Jonasdottir, A., Besenbacher, S., Kostic, J. P., Fackenthal, J. D., Huo, D., Adebamowo, C., Ogundiran, T., Olson, J. E., Fredericksen, Z. S., Wang, X., Look, M. P., Sieuwerts, A. M., Martens, J. W. M., ... Stefansson, K. (2010). Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus. PLoS Genetics, 6(7). https://doi.org/10.1371/journal.pgen.1001029

@article{db2fe3028311496fa6325baaca4e9ce4,

title = "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 = 1.2x10(-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 Patrick Sulem and Carlo Zanon and Gudjonsson, {Sigurjon A.} and Gudmar Thorleifsson and Agnar Helgason and Aslaug Jonasdottir and Soren Besenbacher and Kostic, {Jelena P.} and Fackenthal, {James D.} and Dezheng Huo and Clement Adebamowo and Temidayo Ogundiran and Olson, {Janet E.} and Fredericksen, {Zachary S.} and Xianshu Wang and Look, {Maxime P.} and Sieuwerts, {Anieta M.} and Martens, {John W. M.} and Isabel Pajares and Garcia-Prats, {Maria D.} and Ramon-Cajal, {Jose M.} and {de Juan}, Ana and Angeles Panadero and Eugenia Ortega and Aben, {Katja K. H.} and Vermeulen, {Sita H.} and Fatemeh Asadzadeh and {van Engelenburg}, {K. C. Anton} and Sara Margolin and Chen-Yang Shen and Pei-Ei Wu and Asta F{\"o}rsti and Per Lenner and Roger Henriksson and Robert Johansson and Kerstin Enquist and Goran Hallmans and Thorvaldur Jonsson and Helgi Sigurdsson and Kristin Alexiusdottir and Julius Gudmundsson and Asgeir Sigurdsson and Frigge, {Michael L.} and Larus Gudmundsson and Kristleifur Kristjansson and Halldorsson, {Bjarni V.} and Unnur Styrkarsdottir and Gulcher, {Jeffrey R.} and Kari Hemminki and Annika Lindblom 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 Unnur Thorsteinsdottir and Thorunn Rafnar and Johannsson, {Oskar T.} and Kari Stefansson",

year = "2010",

doi = "10.1371/journal.pgen.1001029",

language = "English",

volume = "6",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science (PLoS)",

number = "7",

}

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, JWM, Pajares, I, Garcia-Prats, MD, Ramon-Cajal, JM, de Juan, A, Panadero, A, Ortega, E, Aben, KKH, Vermeulen, SH, Asadzadeh, F, van Engelenburg, KCA, Margolin, S, Shen, C-Y, Wu, P-E, 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 2010, 'Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus', PLoS Genetics, vol. 6, no. 7. https://doi.org/10.1371/journal.pgen.1001029

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 - van Engelenburg, K. C. Anton

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, Goran

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

Y1 - 2010

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 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.

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 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.

U2 - 10.1371/journal.pgen.1001029

DO - 10.1371/journal.pgen.1001029

M3 - Article

C2 - 20661439

SN - 1553-7404

VL - 6

JO - PLoS Genetics

JF - PLoS Genetics

IS - 7

ER -

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

Abstract

Subject classification (UKÄ)

UN SDGs

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