Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
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DOI：
10.1371/journal.pgen.1001029
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发表时间：
2010-07-22
期刊：
影响因子：
4.5
通讯作者：
Stefansson K
中科院分区：
文献类型：
--
作者：
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
我们使用了一种我们称之为祖先偏移细化映射的方法来研究rs 2046210 [T]与乳腺癌易感性之间的关联，该关联最初是在中国人群的GWAS中发现的。该基因座位于6q25.1，靠近C6 orf 97和雌激素受体α（ESR 1）基因。我们在中国人中发现了一组与rs 2046210相关的SNPs，但在其他祖先人群中不一定如此，并在亚洲，欧洲和非洲起源的乳腺癌病例与对照样本中对它们进行了基因分型，共10，176例病例和13，286例对照。我们发现，rs 2046210 [T]在欧洲人和非洲人中并不具有显著的乳腺癌风险（OR = 1.04，P = 0.099和OR = 0.98，P = 0.77）。 相反，在这些祖先中，关联信号来自以rs 9397435为代表的一组不太常见的SNP。在欧洲（OR = 1.15，P = 1.2×10−3）、非洲（OR = 1.35，P = 0.014）和亚洲（OR = 1.23，P = 2.9×10−4）人群样本中，发现rs 9397435 [G]等位基因赋予乳腺癌风险。 合并所有血统，OR为1.19（P = 3.9×10 - 7），血统之间没有显着异质性（Phet = 0.36），并且SNP完全解释了每个血统中的关联信号。 携带rs 9397435 [G]的单倍型仅在亚洲人中被rs 2046210 [T]标记。rs 9397435 [G]等位基因与雌激素受体阳性和雌激素受体阴性乳腺癌均相关。使用来自1,000个基因组项目的早期草案数据，我们发现与rs 9397435密切相关的新型SNP（rs77275268）的风险等位基因破坏了已知CTCF结合位点内的部分甲基化CpG序列。这些研究表明，在祖先群体之间转移分析可以提供有价值的解决方案，关联映射。在疾病易感性的全基因组关联研究中，并不特别期望显示关联的基因分型SNP本身是致病性变体。相反，发出信号的SNP更有可能这样做，因为它与致病性变体处于连锁不平衡（LD）状态。当分析转移到另一个祖先的群体时，由于群体之间LD的不同模式，基因分型的SNP和致病性变体之间的标记关系可能被破坏。因此，确定在一个祖先群体中鉴定的易感基因座是否也与另一个祖先群体中的风险相关并不简单。此外，不同的模式之间的LD祖先群体可以用来获得分辨率的遗传作图。我们将这种方法称为祖先迁移细化映射。在这里，我们将其应用于最初在中国人群中描述的雌激素受体α基因附近的乳腺癌风险变体。我们表明，最初描述的SNP rs 2046210和致病性变体之间的标记关系在欧洲人和非洲人中没有维持。我们确定了一个SNP，rs 9397435，与亚洲，欧洲和非洲血统人群中的乳腺癌风险相关。
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 α (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 = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 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. In genome-wide association studies of disease susceptibility, there is no particular expectation that a genotyped SNP showing an association is itself a pathogenic variant. Rather, it is more likely that a SNP giving a signal does so because it is in linkage disequilibrium (LD) with a pathogenic variant. When the analysis is shifted to a population of another ancestry, the tagging relationship between the genotyped SNP and the pathogenic variant may be disrupted, due to differing patterns of LD between populations. Thus, it is not straightforward to determine whether a susceptibility locus identified in one ancestral population is also associated with risk in another. Moreover, the differing patterns of LD between ancestral populations can be used to gain resolution in genetic mapping. We refer to this approach as ancestry-shift refinement mapping. Here, we apply it to a breast cancer risk variant near the estrogen receptor α gene that was initially described in a Chinese population. We show that the tagging relationship between the originally described SNP rs2046210 and the pathogenic variant(s) is not maintained in Europeans and Africans. We identify a SNP, rs9397435, that is associated with breast cancer risk in populations of Asian, European, and African ancestry.
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影响因子：
56.9
作者：
McVean, GAT;Myers, SR;Donnelly, P
通讯作者：
Donnelly, P
影响因子：
30.8
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稀有变体会产生整个基因组的关联。
影响因子：
9.8
作者：
Dickson SP;Wang K;Krantz I;Hakonarson H;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
3.8
作者：
Osborne, CK
通讯作者：
Osborne, CK