A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer
A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer
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DOI：
10.1007/s00439-013-1390-4
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发表时间：
2014-05-01
期刊：
影响因子：
5.3
通讯作者：
Ruiz-Ponte, C.
中科院分区：
文献类型：
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作者：
Fernandez-Rozadilla, C.;Cazier, J. B.;Ruiz-Ponte, C.
结直肠癌（CRC）是一种复杂的疾病，因此其发展由环境因素和遗传变异的组合决定。尽管SNP变异的全基因组关联研究（GWAS）迄今已方便地鉴定出20种遗传变异，但观察到的遗传性中有很大一部分尚未得到解释。常见的拷贝数变异（CNVs）是最重要的基因组变异来源之一，因此是解释部分缺失遗传部分的潜在来源。因此，我们对CNVs进行了GWAS，以探索常见结构变异与CRC发展之间的关系。GWAS的第1阶段包括来自西班牙队列的881例病例和667例对照。在I期研究中，通过定量PCR验证了可能与CRC相关的每种常见CNV的拷贝数状态。随后，选择SNPs作为第二阶段复制的经验证的CNV的代理（1，342例西班牙病例和1，874例西班牙对照）。发现四种常见的CNV与CRC相关，并在II期进一步复制。最后，我们发现SNP rs 1944682标记11 q11 CNV，与CRC易感性名义上相关（p值= 0.039; OR = 1.122）。该基因座先前与极端肥胖表型相关，这可能表明体重与CRC易感性之间的关系。
Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.