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系统识别跨表达数量性状基因座(trans eQTLs)作为已知疾病关联的潜在驱动因素。

Systematic identification of trans eQTLs as putative drivers of known disease associations.

机构信息

Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.

Department of Internal Medicine, Erasmus Medical Centre Rotterdam, the Netherlands.

出版信息

Nat Genet. 2013 Oct;45(10):1238-1243. doi: 10.1038/ng.2756. Epub 2013 Sep 8.

DOI:10.1038/ng.2756
PMID:24013639
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3991562/
Abstract

Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

摘要

鉴定与疾病相关的单核苷酸多态性的下游效应具有挑战性。为了帮助克服这个问题，我们在来自 5311 名未转化的外周血样本中进行了表达数量性状基因座 (eQTL) 荟萃分析，并在 2775 名个体中进行了复制。我们鉴定并复制了 233 个与全基因组显著相关的复杂性状相关的 SNP 的跨 eQTL（反映了 103 个独立的基因座）。其中一些 SNP 会影响多个在疾病个体中发生改变的反式基因：rs4917014，先前与系统性红斑狼疮 (SLE) 相关，改变了 C1QB 和五个 I 型干扰素反应基因的基因表达，这都是 SLE 的标志。DeepSAGE RNA 测序表明，rs4917014 在顺式强烈改变 IKZF1 的 3'UTR 水平，对反式调节基因的染色质免疫沉淀和测序分析表明 IKZF1 是因果基因。与胆固醇代谢和 1 型糖尿病相关的变异也表现出类似的现象，表明大规模的 eQTL 图谱提供了对许多与性状相关的变异的下游效应的深入了解。

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Systematic identification of trans eQTLs as putative drivers of known disease associations.

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本文引用的文献

[1]
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Nat Genet. 2012-3-25

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Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

PLoS Genet. 2011-12-1

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