基于人类表型组-基因组组装网络的模块性实现疾病基因的预测与优先级排序

Towards prediction and prioritization of disease genes by the modularity of human phenome-genome assembled network.

作者信息

Jiang Jeffrey Q, Dress Andreas W M, Chen Ming

机构信息

CAS-MPG Partner Institute for Computational Biology, Shanghai 200031, China.

出版信息

J Integr Bioinform. 2010 Nov 22;7(2):425. doi: 10.2390/biecoll-jib-2010-149.

Abstract

Empirical clinical studies on the human interactome and phenome not only illustrates prevalent phenotypic overlap and genetic overlap between diseases, but also reveals a modular organization of the genetic landscape of human disease, providing new opportunities to reduce the complexity in dissecting the phenotype-genotype association. We here introduce a network-module based method towards phenotype-genotype association inference and disease gene identification. This approach incorporates protein-protein interaction network, phenotype similarity network and known phenotype-genotype associations into an assembled network. We then decomposes the resulted network into modules (or communities) wherein we identified and prioritized the disease genes from the candidates within the loci associated with the query disease using a linear regression model and concordance score. For the known phenotype-gene associations in the OMIM database, we used the leave-one-out validation to evaluate the feasibility of our method, and successfully ranked known disease genes at top 1 in 887 out of 1807 cases. Moreover, applying this approach on 850 OMIM loci characterized by an unknown molecular basis, we propose high-probability candidates for 81 genetic diseases.

摘要

关于人类相互作用组和表型组的实证临床研究不仅阐明了疾病之间普遍存在的表型重叠和基因重叠,还揭示了人类疾病遗传景观的模块化组织,为降低剖析表型-基因型关联的复杂性提供了新机会。我们在此介绍一种基于网络模块的方法来进行表型-基因型关联推断和疾病基因识别。这种方法将蛋白质-蛋白质相互作用网络、表型相似性网络和已知的表型-基因型关联整合到一个组装网络中。然后,我们将所得网络分解为模块(或群落),在其中使用线性回归模型和一致性得分从与查询疾病相关的基因座内的候选基因中识别疾病基因并对其进行优先级排序。对于OMIM数据库中已知的表型-基因关联,我们使用留一法验证来评估我们方法的可行性,并在1807个案例中的887个案例中成功将已知疾病基因排在首位。此外,将这种方法应用于850个分子基础未知的OMIM基因座,我们为81种遗传疾病提出了高概率候选基因。

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