Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology.
Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology.
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DOI：
10.1371/journal.pgen.1001273
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发表时间：
2011-01-13
期刊：
影响因子：
4.5
通讯作者：
Daly MJ
中科院分区：
文献类型：
--
作者：
Rossin EJ;Lage K;Raychaudhuri S;Xavier RJ;Tatar D;Benita Y;International Inflammatory Bowel Disease Genetics Constortium;Cotsapas C;Daly MJ
全基因组关联研究（GWAS）已明确了150多个基因组区域，这些区域无疑包含易导致免疫介导疾病的变异。然而，从这些观察结果推断疾病生物学取决于我们发现这些风险变异所扰乱的分子过程的能力。此前已经观察到，对于同一孟德尔疾病，携带致病突变的不同基因往往会发生物理相互作用。我们试图评估在复杂疾病中强关联位点内的基因在多大程度上也是如此。利用在类风湿关节炎（RA）和克罗恩病（CD）的GWAS中确定的位点集，我们为相关位点内的基因构建了蛋白质 - 蛋白质相互作用（PPI）网络，并发现相关基因的蛋白质产物之间存在大量的物理相互作用。我们应用多种排列方法来表明这些网络的连接比随机预期更为紧密。为了确认生物学相关性，我们表明网络的组成部分往往在与相关表型有关的相似组织中表达，这表明该网络揭示了受风险位点扰乱的共同潜在过程。此外，我们通过证明在这些网络中的蛋白质（不在已确认的疾病相关位点列表中编码）在扩展的GWAS分析中与相关表型的关联性显著富集，表明RA和CD网络具有预测能力。最后，我们在3种非免疫性状中测试我们的方法，以评估其对一般复杂性状的适用性。我们发现与身高和血脂水平相关的位点中的基因组装成显著连接的网络，但在2型糖尿病（T2D）位点中未检测到超出随机的过度连接。综上所述，我们的结果证明，对于在此研究的许多复杂疾病，常见的遗传关联暗示了编码以优先方式发生物理相互作用的蛋白质的区域，这与在孟德尔疾病中的观察结果一致。
全基因组关联研究已经发现了数百种与复杂疾病相关的DNA变化。这些研究的最终期望是理解疾病生物学；然而，这个目标并不容易实现，因为每种疾病都产生了大量的关联，每个关联都指向基因组的一个区域，而不是一个特定的致病突变。据推测，致病变异影响常见分子过程的组成部分，而理解患者中受扰乱的疾病生物学的第一步是确定与疾病相关的区域之间的联系。由于在许多孟德尔疾病中已经报道致病基因的蛋白质产物往往会相互物理结合，我们选择利用已知的蛋白质 - 蛋白质相互作用来解决这个问题，以测试在五个复杂性状相关位点中的基因产物是否相互结合。我们应用了几种排列方法，并在其中四个性状中发现了非常显著的连接性。在克罗恩病和类风湿关节炎中，我们能够表明这些基因是共表达的，并且网络中出现的其他蛋白质与疾病的关联性是富集的。这些发现表明，对于在此研究的复杂性状，相关位点包含影响常见分子过程的变异，而不是每个关联所特有的不同机制。
Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein–protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease. Genome-wide association studies have uncovered hundreds of DNA changes associated with complex disease. The ultimate promise of these studies is the understanding of disease biology; this goal, however, is not easily achieved because each disease has yielded numerous associations, each one pointing to a region of the genome, rather than a specific causal mutation. Presumably, the causal variants affect components of common molecular processes, and a first step in understanding the disease biology perturbed in patients is to identify connections among regions associated to disease. Since it has been reported in numerous Mendelian diseases that protein products of causal genes tend to physically bind each other, we chose to approach this problem using known protein–protein interactions to test whether any of the products of genes in five complex trait-associated loci bind each other. We applied several permutation methods and find robustly significant connectivity within four of the traits. In Crohn's disease and rheumatoid arthritis, we are able to show that these genes are co-expressed and that other proteins emerging in the network are enriched for association to disease. These findings suggest that, for the complex traits studied here, associated loci contain variants that affect common molecular processes, rather than distinct mechanisms specific to each association.
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14.9
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Chatr-aryamontri, Andrew;Ceol, Arnaud;Palazzi, Luisa Montecchi;Nardelli, Giuliano;Schneider, Maria Victoria;Castagnoli, Luisa;Cesareni, Gianni
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Cesareni, Gianni
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Barrett, Jeffrey C.;Lee, James C.;Lees, Charles W.;Prescott, Natalie J.;Anderson, Carl A.;Phillips, Anne;Wesley, Emma;Parnell, Kirstie;Zhang, Hu;Drummond, Hazel;Nimmo, Elaine R.;Massey, Dunecan;Blaszczyk, Kasia;Elliott, Timothy;Cotterill, Lynn;Dallal, Helen;Lobo, Alan J.;Mowat, Craig;Sanderson, Jeremy D.;Jewell, Derek P.;Newman, William G.;Edwards, Cathryn;Ahmad, Tariq;Mansfield, John C.;Satsangi, Jack;Parkes, Miles;Mathew, Christopher G.;Donnelly, Peter;Peltonen, Leena;Blackwell, Jenefer M.;Bramon, Elvira;Brown, Matthew A.;Casas, Juan P.;Corvin, Aiden;Craddock, Nicholas;Deloukas, Panos;Duncanson, Audrey;Jankowski, Janusz;Markus, Hugh S.;McCarthy, Mark I.;Palmer, Colin N. A.;Plomin, Robert;Rautanen, Anna;Sawcer, Stephen J.;Samani, Nilesh;Trembath, Richard C.;Viswanathan, Ananth C.;Wood, Nicholas;Spencer, Chris C. A.;Bellenguez, Celine;Davison, Daniel;Freeman, Colin;Strange, Amy;Langford, Cordelia;Hunt, Sarah E.;Edkins, Sarah;Gwilliam, Rhian;Blackburn, Hannah;Bumpstead, Suzannah J.;Dronov, Serge;Gillman, Matthew;Gray, Emma;Hammond, Naomi;Jayakumar, Alagurevathi;McCann, Owen T.;Liddle, Jennifer;Perez, Marc L.;Potter, Simon C.;Ravindrarajah, Radhi;Ricketts, Michelle;Waller, Matthew;Weston, Paul;Widaa, Sara;Whittaker, Pamela;Attwood, Antony P.;Stephens, Jonathan;Sambrook, Jennifer;Ouwehand, Willem H.;McArdle, Wendy L.;Ring, Susan M.;Strachan, David P.
通讯作者：
Strachan, David P.
影响因子：
30.8
作者：
De Jager, Philip L.;Jia, Xiaoming;Wang, Joanne;de Bakker, Paul I. W.;Ottoboni, Linda;Aggarwal, Neelum T.;Piccio, Laura;Raychaudhuri, Soumya;Tran, Dong;Aubin, Cristin;Briskin, Rebeccah;Romano, Susan;Baranzini, Sergio E.;McCauley, Jacob L.;Pericak-Vance, Margaret A.;Haines, Jonathan L.;Gibson, Rachel A.;Naeglin, Yvonne;Uitdehaag, Bernard;Matthews, Paul M.;Kappos, Ludwig;Polman, Chris;McArdle, Wendy L.;Strachan, David P.;Evans, Denis;Cross, Anne H.;Daly, Mark J.;Compston, Alastair;Sawcer, Stephen J.;Weiner, Howard L.;Hauser, Stephen L.;Hafler, David A.;Oksenberg, Jorge R.
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