Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A:: Implications for linkage-disequilibrium gene mapping
Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A:: Implications for linkage-disequilibrium gene mapping
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DOI：
10.1086/378098
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发表时间：
2003-09-01
影响因子：
9.8
通讯作者：
Goldstein, DB
中科院分区：
文献类型：
--
作者：
Weale, ME;Depondt, C;Goldstein, DB
关联研究被广泛认为是发现影响遗传复杂性状（如常见疾病及其治疗反应）的多态性的最有前途的方法。因此，相当大的兴趣最近集中在开发有效筛选基因组区域或整个基因组中与复杂表型相关的基因变体的方法上。在这个搜索中的一个关键因素是使用连锁不平衡，以获得最大的信息，从分型的高度信息的单核苷酸多态性（SNP）标记，现在通常被称为“标签SNP”（tSNPs）的一个选定的子集。连锁不平衡基因定位最常见的方法可能包括三步程序：（1）表征候选基因或感兴趣的基因组区域中的单倍型结构，（2）鉴定足以代表最常见单倍型的tSNP，（3）临床材料中的tSNP分型。tSNPs的早期定义集中在他们解释的单倍型多样性的数量上。然而，为了选择在遗传关联研究中具有最大功率的tSNP，我们已经开发了基于关联度量的优化标准，并将其与基于单倍型多样性的其他标准进行了比较。为了评估完整的程序，并评估如何以及所选择的标签可能执行，我们已经确定了单倍型结构，并评估了在SCN 1A基因，一个重要的候选基因散发性癫痫tSNPs。我们发现，少至四个tSNP预测保持一致的高值与基因中的所有其他常见的SNP，这表明标签可以用于关联研究，只有一个适度的降低功率相对于所有常见的SNP的直接测定。这意味着，一旦确定了tSNP，就可以通过可管理的实验努力来筛选数百个候选基因中的变异。然而，我们的研究结果也表明，在一个人群中发现的tSNPs不一定在另一个人群中表现良好，这表明初步研究，以确定tSNPs和后期的病例对照研究应在同一人群中进行。我们的研究结果还表明，tSNPs将不容易识别不一致的SNPs，这是重要的区别，但显然短的系谱分支。这可能会显着复杂的标记方法的表型的影响，变异经历了积极的选择。
Association studies are widely seen as the most promising approach for finding polymorphisms that influence genetically complex traits, such as common diseases and responses to their treatment. Considerable interest has therefore recently focused on the development of methods that efficiently screen genomic regions or whole genomes for gene variants associated with complex phenotypes. One key element in this search is the use of linkage disequilibrium to gain maximal information from typing a selected subset of highly informative single-nucleotide polymorphism ( SNP) markers, now often called "tagging SNPs" (tSNPs). Probably the most common approach to linkage-disequilibrium gene mapping involves a three-step program: ( 1) characterization of the haplotype structure in candidate genes or genomic regions of interest, ( 2) identification of tSNPs sufficient to represent the most common haplotypes, and ( 3) typing of tSNPs in clinical material. Early definitions of tSNPs focused on the amount of haplotype diversity that they explained. To select tSNPs that would have maximal power in a genetic association study, however, we have developed optimization criteria based on the measure of association and have compared these with other criteria based on the haplotype diversity. To evaluate the full program and to assess how well the selected tags are likely to perform, we have determined the haplotype structure and have assessed tSNPs in the SCN1A gene, an important candidate gene for sporadic epilepsy. We find that as few as four tSNPs are predicted to maintain a consistently high value with all other common SNPs in the gene, indicating that the tags could be used in an association study with only a modest reduction in power relative to direct assays of all common SNPs. This implies that very large case-control studies can be screened for variation in hundreds of candidate genes with manageable experimental effort, once tSNPs are identified. However, our results also show that tSNPs identified in one population may not necessarily perform well in another, indicating that the preliminary study to identify tSNPs and the later case-control study should be performed in the same population. Our results also indicate that tSNPs will not easily identify discrepant SNPs, which lie on importantly discriminating but apparently short genealogical branches. This could significantly complicate tagging approaches for phenotypes influenced by variants that have experienced positive selection.