Integration of disease-specific single nucleotide polymorphisms, expression quantitative trait loci and coexpression networks reveal novel candidate genes for type 2 diabetes.
Integration of disease-specific single nucleotide polymorphisms, expression quantitative trait loci and coexpression networks reveal novel candidate genes for type 2 diabetes.
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DOI：
10.1007/s00125-012-2568-3
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发表时间：
2012-08
期刊：
影响因子：
8.2
通讯作者：
Butte, A. J.
中科院分区：
文献类型：
--
作者：
Kang, H. P.;Yang, X.;Chen, R.;Zhang, B.;Corona, E.;Schadt, E. E.;Butte, A. J.
虽然全基因组关联研究(GWAS)已经成功地识别了与各种疾病相关的新变异，但要确定这些关联背后的生物学机制要困难得多。表达数量性状基因座(EQTL)通过将单核苷酸多态(SNPs)与基因表达联系起来，为这些数据提供了另一个维度。我们假设，将已知与2型糖尿病相关的SNPs与eQTL和共表达网络相结合，将能够发现新的2型糖尿病候选基因。我们在两个或多个独立的GWAS中选择了32个与2型糖尿病相关的SNP。我们使用从1008名病态肥胖患者收集的基因型和基因表达数据中映射的先前描述的eQTL来寻找与这些SNPs相关的表达基因。我们将这些基因链接到共表达模块，并使用倒数和分数对这些模块中的其他基因进行排序。我们发现了62个与2型糖尿病SNPs相关的表达基因。我们通过组合eQTL数据集将共表达模块中排名较高的基因与SNPs联系起来，从而验证了我们的方法。我们发现，在惠康信托病例对照联盟(WTCCC，p = 0.026)和基因环境协会研究(日内瓦，p = 0.042)的数据中，这种方法突出显示的eQTL显著丰富了与2型糖尿病相关的eQTL，从而验证了我们的方法。许多排名较高的基因也参与了胰岛素、葡萄糖或脂类的调节或代谢。我们设计了一种新的方法，涉及整合不同模式的数据集，以发现新的2型糖尿病候选基因。
While genome-wide association studies (GWASs) have been successful in identifying novel variants associated with various diseases, it has been much more difficult to determine the biological mechanisms underlying these associations. Expression quantitative trait loci (eQTL) provide another dimension to these data by associating single nucleotide polymorphisms (SNPs) with gene expression. We hypothesised that integrating SNPs known to be associated with type 2 diabetes with eQTLs and coexpression networks would enable the discovery of novel candidate genes for type 2 diabetes. We selected 32 SNPs associated with type 2 diabetes in two or more independent GWASs. We used previously described eQTLs mapped from genotype and gene expression data collected from 1,008 morbidly obese patients to find genes with expression associated with these SNPs. We linked these genes to coexpression modules, and ranked the other genes in these modules using an inverse sum score. We found 62 genes with expression associated with type 2 diabetes SNPs. We validated our method by linking highly ranked genes in the coexpression modules back to SNPs through a combined eQTL dataset. We showed that the eQTLs highlighted by this method are significantly enriched for association with type 2 diabetes in data from the Wellcome Trust Case Control Consortium (WTCCC, p = 0.026) and the Gene Environment Association Studies (GENEVA, p = 0.042), validating our approach. Many of the highly ranked genes are also involved in the regulation or metabolism of insulin, glucose or lipids. We have devised a novel method, involving the integration of datasets of different modalities, to discover novel candidate genes for type 2 diabetes.
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影响因子：
11
作者：
Richards AL;Jones L;Moskvina V;Kirov G;Gejman PV;Levinson DF;Sanders AR;Molecular Genetics of Schizophrenia Collaboration (MGS);International Schizophrenia Consortium (ISC);Purcell S;Visscher PM;Craddock N;Owen MJ;Holmans P;O'Donovan MC
通讯作者：
O'Donovan MC
影响因子：
9.8
作者：
Schadt EE;Molony C;Chudin E;Hao K;Yang X;Lum PY;Kasarskis A;Zhang B;Wang S;Suver C;Zhu J;Millstein J;Sieberts S;Lamb J;GuhaThakurta D;Derry J;Storey JD;Avila-Campillo I;Kruger MJ;Johnson JM;Rohl CA;van Nas A;Mehrabian M;Drake TA;Lusis AJ;Smith RC;Guengerich FP;Strom SC;Schuetz E;Rushmore TH;Ulrich R
通讯作者：
Ulrich R
影响因子：
7.7
作者：
Takeuchi F;Serizawa M;Yamamoto K;Fujisawa T;Nakashima E;Ohnaka K;Ikegami H;Sugiyama T;Katsuya T;Miyagishi M;Nakashima N;Nawata H;Nakamura J;Kono S;Takayanagi R;Kato N
通讯作者：
Kato N
影响因子：
5.3
作者：
Bray, NJ;Buckland, PR;O'Donovan, MC
通讯作者：
O'Donovan, MC
鉴定驱动小鼠F2间交叉中心血管和代谢表型的基因和网络。
影响因子：
3.7
作者：
Derry JM;Zhong H;Molony C;MacNeil D;Guhathakurta D;Zhang B;Mudgett J;Small K;El Fertak L;Guimond A;Selloum M;Zhao W;Champy MF;Monassier L;Vogt T;Cully D;Kasarskis A;Schadt EE
通讯作者：
Schadt EE