Systematic identification of trans eQTLs as putative drivers of known disease associations.
Systematic identification of trans eQTLs as putative drivers of known disease associations.
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DOI：
10.1038/ng.2756
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发表时间：
2013-10
期刊：
影响因子：
30.8
通讯作者：
Franke, Lude
中科院分区：
文献类型：
--
作者：
Westra, Harm-Jan;Peters, Marjolein J.;Esko, Tonu;Yaghootkar, Hanieh;Schurmann, Claudia;Kettunen, Johannes;Christiansen, Mark W.;Fairfax, Benjamin P.;Schramm, Katharina;Powell, Joseph E.;Zhernakova, Alexandra;Zhernakova, Daria V.;Veldink, Jan H.;Van den Berg, Leonard H.;Karjalainen, Juha;Withoff, Sebo;Uitterlinden, Andre G.;Hofman, Albert;Rivadeneira, Fernando;'t Hoen, Peter A. C.;Reinmaa, Eva;Fischer, Krista;Nelis, Mari;Milani, Lili;Melzer, David;Ferrucci, Luigi;Singleton, Andrew B.;Hernandez, Dena G.;Nalls, Michael A.;Homuth, Georg;Nauck, Matthias;Radke, Doerte;Voelker, Uwe;Perola, Markus;Salomaa, Veikko;Brody, Jennifer;Suchy-Dicey, Astrid;Gharib, Sina A.;Enquobahrie, Daniel A.;Lumley, Thomas;Montgomery, Grant W.;Makino, Seiko;Prokisch, Holger;Herder, Christian;Roden, Michael;Grallert, Harald;Meitinger, Thomas;Strauch, Konstantin;Li, Yang;Jansen, Ritsert C.;Visscher, Peter M.;Knight, Julian C.;Psaty, Bruce M.;Ripatti, Samuli;Teumer, Alexander;Frayling, Timothy M.;Metspalu, Andres;van Meurs, Joyce B. J.;Franke, Lude
确定疾病相关的单核苷酸多态性（SNP）的下游效应具有挑战性：致病基因通常是未知的，或者不清楚SNP如何影响致病基因，因此很难设计揭示功能后果的实验。为了帮助克服这个问题，我们进行了迄今为止在5，311个个体的非转化外周血样本中报道的最大表达数量性状基因座（eQTL）荟萃分析，并在2，775个个体中进行了重复。我们确定并复制了233个SNPs（反映103个独立位点）的trans-eQTL，这些SNPs以前与全基因组意义上的复杂性状相关。虽然我们没有研究特定的患者队列，但我们确定了影响多个已知在患者中显著改变的转基因的性状相关SNP：例如，系统性红斑狼疮（SLE）SNP rs 4917014改变了C1 QB和5个1型干扰素应答基因，这两个基因都是SLE的标志。随后对这些转基因的ChIP-seq数据分析表明转录因子IKZF 1是该基因座的致病基因，DeepSAGE RNA测序显示rs 4917014强烈改变了IKZF 1的3' UTR水平。与胆固醇代谢和1型糖尿病相关的变异表现出类似的现象，表明大规模eQTL定位提供了对许多性状相关变异的下游效应的洞察。
Identifying the downstream effects of disease-associated single nucleotide polymorphisms (SNPs) is challenging: the causal gene is often unknown or it is unclear how the SNP affects the causal gene, making it difficult to design experiments that reveal functional consequences. To help overcome this problem, we performed the largest expression quantitative trait locus (eQTL) meta-analysis so far reported in non-transformed peripheral blood samples of 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. Although we did not study specific patient cohorts, we identified trait-associated SNPs that affect multiple trans-genes that are known to be markedly altered in patients: for example, systemic lupus erythematosus (SLE) SNP rs4917014 altered C1QB and five type 1 interferon response genes, both hallmarks of SLE. Subsequent ChIP-seq data analysis on these trans-genes implicated transcription factor IKZF1 as the causal gene at this locus, with DeepSAGE RNA-sequencing revealing that rs4917014 strongly alters 3’ UTR levels of IKZF1. 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.
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影响因子：
3.7
作者：
Alberts, Rudi;Terpstra, Peter;Li, Yang;Breitling, Rainer;Nap, Jan-Peter;Jansen, Ritsert C.
通讯作者：
Jansen, Ritsert C.
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
中国汉族人群的全基因组关联研究确定了系统性红斑狼疮的九个新易感位点
影响因子：
30.8
作者：
Han, Jian-Wen;Zheng, Hou-Feng;Zhang, Xue-Jun
通讯作者：
Zhang, Xue-Jun