Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.
Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.
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DOI：
10.1371/journal.pgen.1002197
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Franke L
中科院分区：
文献类型：
--
作者：
Fehrmann RS;Jansen RC;Veldink JH;Westra HJ;Arends D;Bonder MJ;Fu J;Deelen P;Groen HJ;Smolonska A;Weersma RK;Hofstra RM;Buurman WA;Rensen S;Wolfs MG;Platteel M;Zhernakova A;Elbers CC;Festen EM;Trynka G;Hofker MH;Saris CG;Ophoff RA;van den Berg LH;van Heel DA;Wijmenga C;Te Meerman GJ;Franke L
对于许多复杂的性状，已经发现与遗传变异有关。然而，目前还不清楚这些变异是通过哪种下游机制导致这些表型的。了解这些中间步骤对了解发病机制至关重要，同时也为潜在的药物干预提供线索。在这里，我们依靠自然的人类遗传变异来确定这些变异对1469名非亲属个体全外周血中转基因表达（表达数量性状位点定位，eQTL）的影响。我们研究了1167个已发表的与性状或疾病相关的snp，观察了113个不同基因的反式eqtl效应，其中46个在1490个不同个体的单核细胞中复制，18个在包括皮下脂肪、内脏脂肪、肝组织和肌肉组织的较小数据集中复制。HLA单核苷酸多态性（snp）在反式eqtl中富集了10倍：HLA中48%的反式作用snp图谱，包括影响反式候选基因AOAH和TRBV18的溃疡性结肠炎易感性变异。我们发现了18对与相同表型相关的非连锁snp，并影响相同转基因的表达（比预期多21倍，P<10−16）。这在平均血小板体积（MPV）方面尤为明显：两个独立的snp显著影响众所周知的凝血基因GP9和F13A1，也影响C19orf33、SAMD14、VCL和GNG11。其中一些snp对下游转基因的影响比对最终表型的影响要大得多，这支持了这些snp对表达的影响似乎不是多因素的概念。因此，这些反式eqtl很可能代表了一些将遗传变异与其最终复杂表型结果联系起来的中间基因。人们发现许多基因变异与疾病有关。然而，对于许多这些遗传变异，尚不清楚它们如何对最终的表型产生影响。我们研究了已知与疾病和复杂表型相关的遗传变异，并评估了这些变异是否也与1469个不相关的全血样本中的基因表达水平相关。对于一些疾病，如1型糖尿病和溃疡性结肠炎，我们观察到遗传变异会影响基因的表达，这在以前没有涉及到。对于复杂性状，如平均血小板体积和平均红细胞体积，我们观察到不同染色体上的独立遗传变异会影响完全相同基因的表达。对于平均血小板体积，这些基因包括已知的凝血基因，但也有功能未知的基因。这些结果表明，通过系统地将遗传变异与基因表达水平相关联，可以识别下游基因，为进一步研究提供重要途径。
For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P<10−16). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes. Many genetic variants have been found associated with diseases. However, for many of these genetic variants, it remains unclear how they exert their effect on the eventual phenotype. We investigated genetic variants that are known to be associated with diseases and complex phenotypes and assessed whether these variants were also associated with gene expression levels in a set of 1,469 unrelated whole blood samples. For several diseases, such as type 1 diabetes and ulcerative colitis, we observed that genetic variants affect the expression of genes, not implicated before. For complex traits, such as mean platelet volume and mean corpuscular volume, we observed that independent genetic variants on different chromosomes influence the expression of exactly the same genes. For mean platelet volume, these genes include well-known blood coagulation genes but also genes with still unknown functions. These results indicate that, by systematically correlating genetic variation with gene expression levels, it is possible to identify downstream genes, which provide important avenues for further research.
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影响因子：
30.8
作者：
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影响因子：
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作者：
Imielinski, Marcin;Baldassano, Robert N.;Griffiths, Anne;Russell, Richard K.;Annese, Vito;Dubinsky, Marla;Kugathasan, Subra;Bradfield, Jonathan P.;Walters, Thomas D.;Sleiman, Patrick;Kim, Cecilia E.;Muise, Aleixo;Wang, Kai;Glessner, Joseph T.;Saeed, Shehzad;Zhang, Haitao;Frackelton, Edward C.;Hou, Cuiping;Flory, James H.;Otieno, George;Chiavacci, Rosetta M.;Grundmeier, Robert;Castro, Massimo;Latiano, Anna;Dallapiccola, Bruno;Stempak, Joanne;Abrams, Debra J.;Taylor, Kent;McGovern, Dermot;Heyman, Melvin B.;Ferry, George D.;Kirschner, Barbara;Lee, Jessica;Essers, Jonah;Grand, Richard;Stephens, Michael;Levine, Arie;Piccoli, David;Van Limbergen, Johan;Cucchiara, Salvatore;Monos, Dimitri S.;Guthery, Stephen L.;Denson, Lee;Wilson, David C.;Grant, Struan F. A.;Daly, Mark;Silverberg, Mark S.;Satsangi, Jack;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon
影响因子：
4.5
作者：
Choy E;Yelensky R;Bonakdar S;Plenge RM;Saxena R;De Jager PL;Shaw SY;Wolfish CS;Slavik JM;Cotsapas C;Rivas M;Dermitzakis ET;Cahir-McFarland E;Kieff E;Hafler D;Daly MJ;Altshuler D
通讯作者：
Altshuler D