Maniatis N, Morton N E, Gibson J, Xu C-F, Hosking L K, Collins A
Human Genetics Division, University of Southampton, Southampton General Hospital, Southampton, UK.
Hum Mol Genet. 2005 Jan 1;14(1):145-53. doi: 10.1093/hmg/ddi019. Epub 2004 Nov 17.
We have developed a simple yet powerful approach for disease gene association mapping by linkage disequilibrium (LD). This method is unique because it applies a model with evolutionary theory that incorporates a parameter for the location of the causal polymorphism. The method exploits LD maps, which assign a location in LD units (LDU) for each marker. This approach is based on single marker tests within a composite likelihood framework, which avoids the heavy Bonferroni correction through multiple testing. As a proof of principle, we tested an 890 kb region flanking the CYP2D6 gene associated with poor drug-metabolizing activity in order to refine the localization of a causal mutation. Previous LD mapping studies using single markers and haplotypes have identified a 390 kb significant region associated with the poor drug-metabolizing phenotype on chromosome 22. None of the 27 Single nucleotide polymorphisms was within the gene. Using a metric LDU map, the commonest functional polymorphism within the gene was located at 14.9 kb from its true location, surrounded within a 95% confidence interval of 172 kb. The kb map had a relative efficiency of 33% compared with the LDU map. Our findings indicate that the support interval and location error are smaller than any published results. Despite the low resolution and the strong LD in the region, our results provide evidence of the substantial utility of LDU maps for disease gene association mapping. These tests are robust to large numbers of markers and are applicable to haplotypes, diplotypes, whole-genome association or candidate region studies.
我们已经开发出一种简单而强大的方法，用于通过连锁不平衡（LD）进行疾病基因关联定位。该方法独特之处在于它应用了一个结合进化理论的模型，该模型纳入了一个因果多态性位置的参数。该方法利用LD图谱，为每个标记在LD单位（LDU）中指定一个位置。这种方法基于复合似然框架内的单标记测试，避免了多重测试带来的繁重的邦费罗尼校正。作为原理验证，我们测试了CYP2D6基因侧翼的一个890 kb区域，该区域与药物代谢活性差有关，以优化因果突变的定位。先前使用单标记和单倍型的LD定位研究已经在22号染色体上确定了一个与药物代谢不良表型相关的390 kb显著区域。27个单核苷酸多态性中没有一个在该基因内。使用度量LDU图谱，该基因内最常见的功能多态性位于距其真实位置14.9 kb处，处于172 kb的95%置信区间内。与LDU图谱相比，kb图谱的相对效率为33%。我们的研究结果表明，支持区间和定位误差比任何已发表的结果都小。尽管该区域分辨率低且LD强，但我们的结果提供了证据，证明LDU图谱在疾病基因关联定位中具有很大的实用性。这些测试对大量标记具有鲁棒性，适用于单倍型、双倍型、全基因组关联或候选区域研究。
