DASH: A Method for Identical-by-Descent Haplotype Mapping Uncovers Association with Recent Variation
DASH: A Method for Identical-by-Descent Haplotype Mapping Uncovers Association with Recent Variation
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DOI：
10.1016/j.ajhg.2011.04.023
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发表时间：
2011-06-10
影响因子：
9.8
通讯作者：
Pe'er, Itsik
中科院分区：
文献类型：
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作者：
Gusev, Alexander;Kenny, Eimear E.;Pe'er, Itsik
影响表型的罕见变异对人类遗传学提出了独特的挑战。虽然全基因组关联研究已经成功地检测到许多常见的因果变异，但它们在识别太罕见或人群特异性而无法从一般参考面板中估算的疾病变异方面能力不足，因此在商业SNP阵列中代表性很差。我们着手克服这些挑战，并通过依赖于长时间的基因组共享（这些基因组共享在血统上是相同的），使用SNP阵列检测疾病与罕见等位基因之间的关联。我们已经开发了一种算法，DASH，它建立在成对相同的血统共享片段的基础上，以推断可能共享单个单倍型的个体集群。DASH构建一个图，其中节点表示个体和基于跨越轨迹的此类段的链接，并使用迭代最小切割算法来识别密集连接的组件。我们通过构建单倍型簇并测试它们的关联性，将DASH应用于模拟数据和不同的GWAS数据集。在模拟中，我们表明，这种方法是显着更强大的比单一标记物检测在一个孤立的人口，是从科斯雷，密克罗尼西亚联邦，并有丰富的IBD，我们提供了正交信息罕见的，最近的变种远交威康信托病例对照联盟（WTCCC）的数据。在这两个队列中，我们确定了一些单倍型关联，在WTCCC数据中有5个这样的基因座，在孤立的基因座中有10个，这些基因座在条件上显著超过任何单个附近的标记。我们在一个独立的欧洲队列中复制了其中一个位点，并确定了集群携带者低通全基因组序列中假定的结构变化。
Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers.