Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium.
Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium.
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DOI：
10.1371/journal.pgen.1006186
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发表时间：
2016-09
期刊：
影响因子：
4.5
通讯作者：
NEIGHBOR Consortium
中科院分区：
文献类型：
--
作者：
Verma SS;Cooke Bailey JN;Lucas A;Bradford Y;Linneman JG;Hauser MA;Pasquale LR;Peissig PL;Brilliant MH;McCarty CA;Haines JL;Wiggs JL;Vrabec TR;Tromp G;Ritchie MD;eMERGE Network;NEIGHBOR Consortium
原发性开角型青光眼(POAG)是一种复杂的疾病，是世界范围内主要的致盲原因之一。全基因组关联研究已经成功地确定了几个与青光眼相关的常见变异；然而，这些变异中的大多数只解释了一小部分遗传风险。除了确定整个基因组中变异的主要效应的标准方法外，人们认为基因-基因相互作用可以通过测试遗传变异之间的相互作用来模拟生物学的复杂性质，从而有助于阐明部分缺失的遗传性。为了解释青光眼的病因，我们首先对从电子病历(EMR)获得的青光眼病例对照样本进行了全基因组关联研究(GWAS)，以建立EMR数据在检测非虚假和相关关联方面的效用；这一分析的目的是确认已知的与青光眼的关联，并验证EMR衍生的青光眼表型。我们来自GWAS的发现表明，POAG中存在几种已知的关联。然后，我们对被发现与青光眼有轻微关联的变异进行了交互分析(SNPs，主效p值为0.01)，并在电子医疗记录和基因组学网络(Emerge)网络数据库中观察到了有趣的发现。然后，对来自Emerge数据(似然比检验，即LRT p-Value<；1e-05)的顶级上位性交互作用的基因进行测试，以在相邻联盟数据集中进行复制。为了重复我们的发现，我们在邻居中进行了基于基因的SNP-SNP交互作用分析，并在发现阶段确定的前17个基因-基因模型中观察到显著的基因-基因交互作用(p值为0.001)。我们发现与POAG相关的基因-基因交互分析的变体解释了Emerge数据集中3.5%的额外遗传方差，高于从以前的GWAS研究中复制的基因中的SNPs解释的额外遗传方差(这在Emerge数据集中仅解释2.1%的方差)；在邻近的数据集中，添加来自基因-基因交互分析的复制的SNPs可以解释3.4%的总方差，而仅GWAS SNPs只能解释2.8%的方差。探索基因-基因的相互作用可能会在适当设计和提供动力的关联研究中探索时，为许多复杂的特征提供额外的见解。原发性开角型青光眼(POAG)的复杂性使研究人员探索了遗传结构，并使用了许多不同的研究设计来寻找缺失的遗传性。在过去的十年里，已经进行了许多研究来解释POAG的病因；然而，很大比例的估计遗传力仍然没有被解释。GWA对POAG的研究已经确定了重要的关联，但这些关联只解释了遗传风险的一小部分(优势比在1-3之间)。在这篇文章中，我们试图确认到目前为止在EMR数据中发现的青光眼表型与全基因组范围内的主要显著关联，以努力表明EMR数据可以成为寻找影响POAG易感性的遗传变异的强大资源。接下来，我们测试了统计交互作用，这可以作为解释POAG遗传性的一个重要工具。我们使用一个经过边际主效应分析筛选的简化变量列表来寻找上位性交互作用。我们介绍了在Emerge和Neighbor财团数据中进行的基于基因的交互分析的复制结果。使用来自各种公开数据库的表达数据和注释，在我们的分析中复制的最重要的基因显示在眼睛和小梁网络中表达。对遗传方差估计的分析表明，这解释了Emerge数据集中5.6%的变异，也解释了相邻数据集中3.4%的变异。
Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies. The complex nature of primary-open angle glaucoma (POAG) has left researchers exploring the genetic architecture and searching for the missing heritability using a number of different study designs. Over the past decade, many studies have been conducted to explain the etiology of POAG; however, a high proportion of estimated heritability still remains unexplained. GWA studies for POAG have identified significant associations but these associations have only explained a small proportion of the genetic risk (odds ratios range between 1–3). In this paper, we sought to confirm the primary genome-wide significant associations that have been discovered so far for glaucoma in phenotypes developed from EMR data in an effort to show that EMR data can be a powerful resource for finding genetic variants influencing POAG susceptibility. Next, we tested for statistical interactions, which can be presented as an important tool in an attempt to explain POAG heritability. We used a reduced list of variants filtered by marginal main effect analysis to look for epistatic interactions. We present our results from replication of gene-based interaction analyses performed in eMERGE and the NEIGHBOR consortium data. Using expression data and annotations from various publicly available databases, the most significant genes that replicated in our analyses show expression in the eye and trabecular meshwork. Analysis for estimation of genetic variance explained by significant associations from previous GWAS and replicated variants from gene-based interactions suggest that these explain 5.6% of variance in eMERGE dataset and also explain 3.4% variance in NEIGHBOR dataset.
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DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
4.5
作者：
Ma L;Brautbar A;Boerwinkle E;Sing CF;Clark AG;Keinan A
通讯作者：
Keinan A
影响因子：
30.8
作者：
Gharahkhani, Puya;Burdon, Kathryn P.;Fogarty, Rhys;Sharma, Shiwani;Hewitt, Alex W.;Martin, Sarah;Law, Matthew H.;Cremin, Katie;Bailey, Jessica N. Cooke;Loomis, Stephanie J.;Pasquale, Louis R.;Haines, Jonathan L.;Hauser, Michael A.;Viswanathan, Ananth C.;McGuffin, Peter;Topouzis, Fotis;Foster, Paul J.;Graham, Stuart L.;Casson, Robert J.;Chehade, Mark;White, Andrew J.;Zhou, Tiger;Souzeau, Emmanuelle;Landers, John;Fitzgerald, Jude T.;Klebe, Sonja;Ruddle, Jonathan B.;Goldberg, Ivan;Healey, Paul R.;Mills, Richard A.;Wang, Jie Jin;Montgomery, Grant W.;Martin, Nicholas G.;Radford-Smith, Graham;Whiteman, David C.;Brown, Matthew A.;Wiggs, Janey L.;Mackey, David A.;Mitchell, Paul;MacGregor, Stuart;Craig, Jamie E.
通讯作者：
Craig, Jamie E.
影响因子：
3.6
作者：
Knauer, Christopher S.;Campbell, Jeffrey E.;Fitzgerald, Lawrence W.
通讯作者：
Fitzgerald, Lawrence W.
影响因子：
30.8
作者：
Lu, Yi;Vitart, Veronique;Burdon, Kathryn P.;Khor, Chiea Chuen;Bykhovskaya, Yelena;Mirshahi, Alireza;Hewitt, Alex W.;Koehn, Demelza;Hysi, Pirro G.;Ramdas, Wishal D.;Zeller, Tanja;Vithana, Eranga N.;Cornes, Belinda K.;Tay, Wan-Ting;Tai, E. Shyong;Cheng, Ching-Yu;Liu, Jianjun;Foo, Jia-Nee;Saw, Seang Mei;Thorleifsson, Gudmar;Stefansson, Kari;Dimasi, David P.;Mills, Richard A.;Mountain, Jenny;Ang, Wei;Hoehn, Rene;Verhoeven, Virginie J. M.;Grus, Franz;Wolfs, Roger;Castagne, Raphaele;Lackner, Karl J.;Springelkamp, Henriet;Yang, Jian;Jonasson, Fridbert;Leung, Dexter Y. L.;Chen, Li J.;Tham, Clement C. Y.;Rudan, Igor;Vatavuk, Zoran;Hayward, Caroline;Gibson, Jane;Cree, Angela J.;MacLeod, Alex;Ennis, Sarah;Polasek, Ozren;Campbell, Harry;Wilson, James F.;Viswanathan, Ananth C.;Fleck, Brian;Li, Xiaohui;Siscovick, David;Taylor, Kent D.;Rotter, Jerome I.;Yazar, Seyhan;Ulmer, Megan;Li, Jun;Yaspan, Brian L.;Ozel, Ayse B.;Richards, Julia E.;Moroi, Sayoko E.;Haines, Jonathan L.;Kang, Jae H.;Pasquale, Louis R.;Allingham, R. Rand;Ashley-Koch, Allison;Mitchell, Paul;Wang, Jie Jin;Wright, Alan F.;Pennell, Craig;Spector, Timothy D.;Young, Terri L.;Klaver, Caroline C. W.;Martin, Nicholas G.;Montgomery, Grant W.;Anderson, Michael G.;Aung, Tin;Willoughby, Colin E.;Wiggs, Janey L.;Pang, Chi P.;Thorsteinsdottir, Unnur;Lotery, Andrew J.;Hammond, Christopher J.;van Duijn, Cornelia M.;Hauser, Michael A.;Rabinowitz, Yaron S.;Pfeiffer, Norbert;Mackey, David A.;Craig, Jamie E.;Macgregor, Stuart;Wong, Tien Y.
通讯作者：
Wong, Tien Y.