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

被引：73

作者：

Stacey, Simon N. ^{[1
]}

Sulem, Patrick ^{[1
]}

Zanon, Carlo ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Thorleifsson, Gudmar ^{[1
]}

Helgason, Agnar ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Besenbacher, Soren ^{[1
]}

Kostic, Jelena P. ^{[1
]}

Fackenthal, James D. ^{[2
,3
]}

Huo, Dezheng ^{[2
,3
]}

Adebamowo, Clement ^{[4
]}

Ogundiran, Temidayo ^{[4
]}

Olson, Janet E. ^{[5
,6
]}

Fredericksen, Zachary S. ^{[5
,6
]}

Wang, Xianshu ^{[5
,6
]}

Look, Maxime P. ^{[7
,8
]}

Sieuwerts, Anieta M. ^{[7
,8
]}

Martens, John W. M. ^{[7
,8
]}

Pajares, Isabel ^{[9
]}

Garcia-Prats, Maria D. ^{[10
]}

Ramon-Cajal, Jose M. ^{[10
]}

de Juan, Ana ^{[11
]}

Panadero, Angeles ^{[12
]}

Ortega, Eugenia ^{[13
]}

Aben, Katja K. H. ^{[14
,15
]}

Vermeulen, Sita H. ^{[15
,16
]}

Asadzadeh, Fatemeh ^{[15
]}

van Engelenburg, K. C. Anton ^{[17
]}

Margolin, Sara ^{[18
]}

Shen, Chen-Yang ^{[19
,20
]}

Wu, Pei-Ei ^{[19
]}

Forsti, Asta ^{[21
,22
]}

Lenner, Per ^{[23
]}

Henriksson, Roger ^{[23
]}

Johansson, Robert ^{[23
]}

Enquist, Kerstin ^{[24
]}

Hallmans, Goran ^{[24
]}

Jonsson, Thorvaldur ^{[25
,26
,27
]}

Sigurdsson, Helgi ^{[25
,26
,27
]}

Alexiusdottir, Kristin ^{[1
,25
,26
,27
]}

Gudmundsson, Julius ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Frigge, Michael L. ^{[1
]}

Gudmundsson, Larus ^{[1
]}

Kristjansson, Kristleifur ^{[1
]}

Halldorsson, Bjarni V. ^{[1
]}

Styrkarsdottir, Unnur ^{[1
]}

Gulcher, Jeffrey R. ^{[1
]}

Hemminki, Kari ^{[21
,22
]}

机构：

[1] DeCODE Genet, Reykjavik, Iceland

[2] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[3] Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA

[4] Univ Ibadan, Div Oncol, Dept Surg, Coll Med,Univ Coll Hosp, Ibadan, Oyo, Nigeria

[5] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[6] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[7] Josephine Nefkens Inst, Erasmus MC Rotterdam, Dept Med Oncol, Rotterdam, Netherlands

[8] Canc Genom Ctr, Rotterdam, Netherlands

[9] Univ Hosp, Div Med Oncol, Zaragoza, Spain

[10] San Jorge Hosp, Div Surg Pathol & Gynecol, Huesca, Spain

[11] Marques de Valdecilla Univ Hosp, Div Med Oncol, Santander, Spain

[12] Hosp Ciudad Coria, Div Med Oncol, Coria, Spain

[13] Univ Hosp, Div Med Oncol, Lerida, Spain

[14] Comprehens Canc Ctr IKO, Nijmegen, Netherlands

[15] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, NL-6525 ED Nijmegen, Netherlands

[16] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[17] Slingeland Hosp, Dept Surg, Doetinchem, Netherlands

[18] Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden

[19] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan

[20] China Med Univ, Grad Inst Environm Sci, Taichung, Taiwan

[21] German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany

[22] Lund Univ, Ctr Primary Hlth Care Res, Clin Res Ctr, Malmo, Sweden

[23] Norrlands Univ Hosp, Dept Oncol, Umea, Sweden

[24] Umea Univ, Dept Publ Hlth & Clin Med Nutr Res, Umea, Sweden

[25] Landspitali Univ Hosp, Dept Oncol, Reykjavik, Iceland

[26] Landspitali Univ Hosp, Dept Surg, Reykjavik, Iceland

[27] Landspitali Univ Hosp, Ctr Canc, Reykjavik, Iceland

[28] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[29] Radboud Univ Nijmegen, Dept Urol, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[30] Nanotechnol Inst Aragon, Hlth Sci Inst, Zaragoza, Spain

来源：

PLOS GENETICS | 2010年 / 6卷 / 07期

基金：

美国国家卫生研究院; 芬兰科学院;

关键词：

GENOME-WIDE ASSOCIATION; CONFER SUSCEPTIBILITY; COMMON VARIANTS; AFRICAN-AMERICAN; CAUSAL VARIANTS; RISK; TAMOXIFEN; DISTINCT; TRAITS; SNPS;

D O I：

10.1371/journal.pgen.1001029

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1 / 12

页数：12

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