Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer
Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer
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DOI：
10.1093/carcin/bgp315
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发表时间：
2010-03-01
期刊：
影响因子：
4.7
通讯作者：
Dragani, Tommaso A.
中科院分区：
文献类型：
--
作者：
Galvan, Antonella;Falvella, Felicia S.;Dragani, Tommaso A.
我们使用全基因组 620 901 单核苷酸多态性 (SNP) 阵列分析和病例对照 DNA 合并方法，分析了一系列年轻（中位年龄 = 52 岁）非吸烟肺癌患者及其未受影响的兄弟姐妹作为对照。我们确定了 82 个假定相关的 SNP，通过个体基因分型重新测试，然后使用同胞传递不平衡测试，指出不一致的同胞系列中有 36 个 SNP 与肺癌风险相关。在以稀有等位基因的加性和可互换效应为特征的多基因模型中对这 36 个 SNP 的分析揭示了风险等位基因携带者状态与癌症病例比例之间高度统计显着的剂量依赖性关联。在基于人群的系列中复制相同的 36 个 SNP，证实了 3 个 SNP 与肺癌的关联，表明表型和遗传异质性在普通人群中肺癌风险的复杂遗传学中发挥着重要作用。
We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.