单核苷酸多态性(SNPs)、单倍型及全基因组连锁不平衡(LD)图谱对关联定位准确性的影响。

Effects of single SNPs, haplotypes, and whole-genome LD maps on accuracy of association mapping.

作者信息

Maniatis Nikolas, Collins Andrew, Morton Newton E

机构信息

Human Genetics Division, University of Southampton, Southampton General Hospital, Southampton, UK.

出版信息

Genet Epidemiol. 2007 Apr;31(3):179-88. doi: 10.1002/gepi.20199.

Abstract

We describe an association mapping approach that utilizes linkage disequilibrium (LD) maps in LD units (LDU). This method uses composite likelihood to combine information from all single marker tests, and applies a model with a parameter for the location of the causal polymorphism. Previous analyses of the poor drug metabolizer phenotype provided evidence of the substantial utility of LDU maps for disease gene association mapping. Using LDU locations for the 27 single nucleotide polymorphisms (SNPs) flanking the CYP2D6 gene on chromosome 22, the most common functional polymorphism within the gene was located at 15 kb from its true location. Here, we examine the performance of this mapping approach by exploiting the high-density LDU map constructed from the HapMap data. Expressing the locations of the 27 SNPs in LDU from the HapMap LDU map, analysis yielded an estimated location that is only 0.3 kb away from the CYP2D6 gene. This supports the use of the high marker density HapMap-derived LDU map for association mapping even though it is derived from a much smaller number of individuals compared to the CYP2D6 sample. We also examine the performance of 2-SNP haplotypes. Using the same modelling procedures and composite likelihood as for single SNPs, the haplotype data provided much poorer localization compared to single SNP analysis. Haplotypes generate more autocorrelation through multiple inclusions of the same SNPs, which could inflate significance in association studies. The results of the present study demonstrate the great potential of the genome HapMap LDU maps for high-resolution mapping of complex phenotypes.

摘要

我们描述了一种关联映射方法,该方法利用以连锁不平衡(LD)单位(LDU)表示的连锁不平衡(LD)图谱。此方法使用复合似然性来合并来自所有单标记测试的信息,并应用一个带有因果多态性位置参数的模型。先前对药物代谢不良表型的分析提供了证据,证明LDU图谱在疾病基因关联映射中具有很大的实用性。利用位于22号染色体上CYP2D6基因两侧的27个单核苷酸多态性(SNP)的LDU位置,该基因内最常见的功能多态性位于距其真实位置15 kb处。在此,我们通过利用从HapMap数据构建的高密度LDU图谱来检验这种映射方法的性能。根据HapMap LDU图谱将27个SNP的位置表示为LDU,分析得出的估计位置与CYP2D6基因仅相距0.3 kb。这支持使用源自HapMap的高标记密度LDU图谱进行关联映射,尽管与CYP2D6样本相比,它来自数量少得多的个体。我们还检验了双SNP单倍型的性能。使用与单SNP相同的建模程序和复合似然性,与单SNP分析相比,单倍型数据提供的定位效果要差得多。单倍型通过多次包含相同的SNP产生更多的自相关性,这可能会在关联研究中夸大显著性。本研究结果证明了基因组HapMap LDU图谱在复杂表型高分辨率映射方面的巨大潜力。

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