Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel.
Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel.
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DOI：
10.1038/ncomms9111
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发表时间：
2015-09-14
影响因子：
16.6
通讯作者：
Soranzo N
中科院分区：
文献类型：
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作者：
Huang J;Howie B;McCarthy S;Memari Y;Walter K;Min JL;Danecek P;Malerba G;Trabetti E;Zheng HF;UK10K Consortium;Gambaro G;Richards JB;Durbin R;Timpson NJ;Marchini J;Soranzo N
从全基因组测序（WGS）创建的参考面板中推断基因型，为增加全基因组阵列的单核苷酸多态性（SNP）含量提供了一种具有成本效益的策略。英国10K队列项目已经生成了一个由3781个低深度测序（平均7倍覆盖）的全基因组组成的数据集，旨在详尽地描述英国人群中低至0.1%的次要等位基因频率的遗传变异。在此，我们证明了这一资源对于提高英国和意大利人群中罕见和低频变异的推断准确性的价值。我们表明，在初始基因型判读之后对WGS参考面板进行重新定相，可以大幅提高推断准确性。我们还提出了一种组合WGS面板以提高变异覆盖度和下游推断准确性的方法，并通过将英国10K项目的7562个WGS单倍型与千人基因组计划的2184个单倍型整合进行了说明。最后，我们引入了一种新的近似方法，该方法在不牺牲罕见变异推断准确性的情况下保持了速度。
推断利用来自SNP阵列的基因型信息来推断缺失标记的基因型。在此，作者表明，与现有方法相比，源自英国10K项目3781个样本全基因组测序的推断参考面板提高了低频变异的推断准确性和覆盖度。
Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants. Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.