Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility loci
Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility loci
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DOI：
10.1086/425870
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发表时间：
2004-12-01
影响因子：
9.8
通讯作者：
Thibodeau, SN
中科院分区：
文献类型：
--
作者：
Schaid, DJ;Guenther, JC;Thibodeau, SN
前列腺癌是男性最常见的癌症之一，长期以来一直被认为是家族聚集性癌症。受影响男性的兄弟和儿子患前列腺癌的风险增加2-3倍。然而，前列腺癌的遗传易感基因的识别一直是极其困难的。尽管许多染色体都有连锁的建议，但最有希望的区域一直很难复制。在这项研究中，我们比较了使用微卫星和使用单核苷酸多态(SNPs)的基因组连锁扫描，对167个家庭的467名前列腺癌患者进行了扫描。对于微卫星，使用具有402个微卫星标记的ABI Prism Linkage Map Set Version 2，而对于SNPs，使用早期访问Affymetrix Maping10K阵列。我们的结果表明，SNPs之间的连锁不平衡(LD)的存在会导致LOD得分的夸大，这似乎是一种人为因素，因为目前的遗传连锁软件要求假设连锁平衡。排除高LD的SNPs后，我们发现了一些微卫星标记没有发现的至少为2.0的新的LOD得分峰：8号染色体，最大无模式LOD评分为2.2；2号染色体，LOD评分为2.1；6号染色体，LOD评分为4.2；以及12号染色体，LOD评分为3.9。6号和12号染色体的LOD分数很难解释，因为它们只发生在染色体的最末端。SNP标记提供的最大收益是连锁信息量的大幅增加，SNPs的平均信息量为61%，而微卫星标记的平均信息量为41%。我们的基因组连锁扫描结果说明了微卫星标记与SNP标记的优缺点。
Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a 2-3-fold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Although the suggestion of linkage has been reported for many chromosomes, the most promising regions have been difficult to replicate. In this study, we compare genome linkage scans using microsatellites with those using single-nucleotide polymorphisms (SNPs), performed in 467 men with prostate cancer from 167 families. For the microsatellites, the ABI Prism Linkage Mapping Set version 2, with 402 microsatellite markers, was used, and, for the SNPs, the Early Access Affymetrix Mapping 10K array was used. Our results show that the presence of linkage disequilibrium (LD) among SNPs can lead to inflated LOD scores, and this seems to be an artifact due to the assumption of linkage equilibrium that is required by the current genetic-linkage software. After excluding SNPs with high LD, we found a number of new LOD-score peaks with values of at least 2.0 that were not found by the microsatellite markers: chromosome 8, with a maximum model-free LOD score of 2.2; chromosome 2, with a LOD score of 2.1; chromosome 6, with a LOD score of 4.2; and chromosome 12, with a LOD score of 3.9. The LOD scores for chromosomes 6 and 12 are difficult to interpret, because they occurred only at the extreme ends of the chromosomes. The greatest gain provided by the SNP markers was a large increase in the linkage information content, with an average information content of 61% for the SNPs, versus an average of 41% for the microsatellite markers. The strengths and weaknesses of microsatellite versus SNP markers are illustrated by the results of our genome linkage scans.