Targeted Sequencing of Lung Function Loci in Chronic Obstructive Pulmonary Disease Cases and Controls.
Targeted Sequencing of Lung Function Loci in Chronic Obstructive Pulmonary Disease Cases and Controls.
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在慢性阻塞性肺部疾病病例和对照中，肺功能基因座的靶向测序。
DOI：
10.1371/journal.pone.0170222
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Tobin MD
中科院分区：
文献类型：
--
作者：
Artigas MS;Wain LV;Shrine N;McKeever TM;UK BiLEVE;Sayers I;Hall IP;Tobin MD
慢性阻塞性肺疾病（COPD）是全球第三大死亡原因;吸烟是COPD的主要风险因素，但遗传因素也是相关因素。用于诊断COPD的肺功能指标的全基因组关联研究（GWAS）已经确定了许多基因座，然而关联信号通常很广泛，这些基因座仅能解释一小部分遗传性。为了研究低等位基因频率的遗传变异与COPD风险的相关性，以帮助精细映射相关信号并解释更多缺失的遗传性，我们对300例COPD病例和300例吸烟对照进行了有针对性的测序研究，其中26个基因座先前报道与肺功能相关。我们使用了一种合并测序方法，12个池，每个池25个个体，使每个样本能够实现高深度（30倍）覆盖。这种合并设计使样本量最大化，因此功效最大化，但在变体识别期间导致挑战，因为罕见变体的测序错误率和次要等位基因频率可能非常相似。出于这个原因，我们采用了严格的质量控制管道进行变异检测，其中包括使用3个独立的调用算法。为了避免假阳性关联，我们还开发了检测具有潜在批次效应的变体的测试，并在进行关联测试之前将其删除。我们测试了单个变异的影响和基因座内罕见变异的组合影响。我们对来自英国生物银行的4,249例COPD病例和11,916例吸烟对照的可用数据（仅67%的折叠方法信号）进行了随访。我们为TNXB和MECOM内和HHIP上游的滑动窗口中罕见变异对COPD风险的联合作用提供了提示性证据。这些发现可以导致对参与COPD发展的分子途径的更好理解。
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; smoking is the main risk factor for COPD, but genetic factors are also relevant contributors. Genome-wide association studies (GWAS) of the lung function measures used in the diagnosis of COPD have identified a number of loci, however association signals are often broad and collectively these loci only explain a small proportion of the heritability. In order to examine the association with COPD risk of genetic variants down to low allele frequencies, to aid fine-mapping of association signals and to explain more of the missing heritability, we undertook a targeted sequencing study in 300 COPD cases and 300 smoking controls for 26 loci previously reported to be associated with lung function. We used a pooled sequencing approach, with 12 pools of 25 individuals each, enabling high depth (30x) coverage per sample to be achieved. This pooled design maximised sample size and therefore power, but led to challenges during variant-calling since sequencing error rates and minor allele frequencies for rare variants can be very similar. For this reason we employed a rigorous quality control pipeline for variant detection which included the use of 3 independent calling algorithms. In order to avoid false positive associations we also developed tests to detect variants with potential batch effects and removed them before undertaking association testing. We tested for the effects of single variants and the combined effect of rare variants within a locus. We followed up the top signals with data available (only 67% of collapsing methods signals) in 4,249 COPD cases and 11,916 smoking controls from UK Biobank. We provide suggestive evidence for the combined effect of rare variants on COPD risk in TNXB and in sliding windows within MECOM and upstream of HHIP. These findings can lead to an improved understanding of the molecular pathways involved in the development of COPD.
影响因子：
3
作者：
Lawrence R;Day-Williams AG;Elliott KS;Morris AP;Zeggini E
通讯作者：
Zeggini E