已知哮喘基因座中有害和调控基因组变异的鉴定
2020/01/02
背景:候选基因和全基因组关联研究已经确定了数百个哮喘风险基因座。然而,大多数相关变异尚未发现具有任何生物学功能,被认为是代表性标志而不是真正的致病突变。我们假设这些相关标志与那些难以捉摸的致病变异之间存在连锁不平衡(LD)。
方法:我们整理了一份综合列表,列出了先前在候选基因和全基因组关联研究中报道过的449种哮喘相关变异。接下来,我们利用1000个人基因组计划的全基因组测序数据,识别了305个独特基因中的所有序列变异。然后,我们计算了已知哮喘变异与每个基因序列变异之间的连锁不平衡,并对识别出的连锁不平衡变异进行注释以确定潜在的有害和/或有功能的变异(即编码或对编码的转录本或蛋白质的调节作用)。
结果:我们在已知哮喘变异体的连锁不平衡 (r2 > 0.6)中确定了10130个变异体。对这些连锁不平衡变体的注释表明,一些变异具有潜在的有害影响,包括移码、交替剪接位置、停止丢失和错误判断。此外,已有24个连锁不平衡的变异被报道作为表达量性状位点(eQTLs)调控基因表达。
结论:这项研究证明了以前与哮喘等复杂疾病相关的许多基因位点不是致病因素,而是疾病的标志物,这些疾病在连锁不平衡中具有难以捉摸的致病变异。我们在此报告了许多与既往已报告的哮喘位点存在连锁不平衡的潜在有害和调节变异。这些报道的连锁不平衡的变异可以解释与哮喘的原始关联信号,并代表这些基因座的真正致病突变。
(Neville MDC, et al. Respir Res. 2018 Dec 12.)
Neville MDC, et al. Respir Res. 2018 Dec 12.
Abstract
BACKGROUND: Candidate gene and genome-wide association studies have identified hundreds of asthma risk loci. The majority of associated variants, however, are not known to have any biological function and are believed to represent markers rather than true causative mutations. We hypothesized that many of these associated markers are in linkage disequilibrium (LD) with the elusive causative variants.
METHODS: We compiled a comprehensive list of 449 asthma-associated variants previously reported in candidate gene and genome-wide association studies. Next, we identified all sequence variants located within the 305 unique genes using whole-genome sequencing data from the 1000 Genomes Project. Then, we calculated the LD between known asthma variants and the sequence variants within each gene. LD variants identified were then annotated to determine those that are potentially deleterious and/or functional (i.e. coding or regulatory effects on the encoded transcript or protein).
RESULTS: We identified 10,130 variants in LD (r2 > 0.6) with known asthma variants. Annotations of these LD variants revealed that several have potentially deleterious effects including frameshift, alternate splice site, stop-lost, and missense. Moreover, 24 of the LD variants have been reported to regulate gene expression as expression quantitative trait loci (eQTLs).
CONCLUSIONS: This study is proof of concept that many of the genetic loci previously associated with complex diseases such as asthma are not causative but represent markers of disease, which are in LD with the elusive causative variants. We hereby report a number of potentially deleterious and regulatory variants that are in LD with the reported asthma loci. These reported LD variants could account for the original association signals with asthma and represent the true causative mutations at these loci.
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欧洲血统个体的中-重度哮喘:一项全基因组关联研究
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