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Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network.

ABSTRACT: BACKGROUND: Protein-protein interaction networks and phenotype similarity information have been synthesized together to discover novel disease-causing genes. Genetic or phenotypic similarities are manifested as certain modularity properties in a phenotype-gene heterogeneous network consisting of the phenotype-phenotype similarity network, protein-protein interaction network and gene-disease association network. However, the quantitative analysis of modularity in the heterogeneous network and its influence on disease-gene discovery are still unaddressed. Furthermore, the genetic correspondence of the disease subtypes can be identified by marking the genes and phenotypes in the phenotype-gene network. We present a novel network inference method to measure the network modularity, and in particular to suggest the subtypes of diseases based on the heterogeneous network. RESULTS: Based on a measure which is introduced to evaluate the closeness between two nodes in the phenotype-gene heterogeneous network, we developed a Hitting-Time-based method, CIPHER-HIT, for assessing the modularity of disease gene predictions and credibly prioritizing disease-causing genes, and then identifying the genetic modules corresponding to potential subtypes of the queried phenotype. The CIPHER-HIT is free to rely on any preset parameters. We found that when taking into account the modularity levels, the CIPHER-HIT method can significantly improve the performance of disease gene predictions, which demonstrates modularity is one of the key features for credible inference of disease genes on the phenotype-gene heterogeneous network. By applying the CIPHER-HIT to the subtype analysis of Breast cancer, we found that the prioritized genes can be divided into two sub-modules, one contains the members of the Fanconi anemia gene family, and the other contains a reported protein complex MRE11/RAD50/NBN. CONCLUSIONS: The phenotype-gene heterogeneous network contains abundant information for not only disease genes discovery but also disease subtypes detection. The CIPHER-HIT method presented here is effective for network inference, particularly on credible prediction of disease genes and the subtype analysis of diseases, for example Breast cancer. This method provides a promising way to analyze heterogeneous biological networks, both globally and locally.

SUBMITTER: Yao X

PROVIDER: S-EPMC3130676 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network.

Yao Xin X Hao Han H Li Yanda Y Li Shao S

BMC systems biology 20110520

<h4>Background</h4>Protein-protein interaction networks and phenotype similarity information have been synthesized together to discover novel disease-causing genes. Genetic or phenotypic similarities are manifested as certain modularity properties in a phenotype-gene heterogeneous network consisting of the phenotype-phenotype similarity network, protein-protein interaction network and gene-disease association network. However, the quantitative analysis of modularity in the heterogeneous network ...[more]

PMID: 21599985

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Project description:The first decade of Genome Wide Association Studies (GWAS) has uncovered a wealth of disease-associated variants. Two important derivations will be the translation of this information into a multiscale understanding of pathogenic variants and leveraging existing data to increase the power of existing and future studies through prioritization. We explore edge prediction on heterogeneous networks--graphs with multiple node and edge types--for accomplishing both tasks. First we constructed a network with 18 node types--genes, diseases, tissues, pathophysiologies, and 14 MSigDB (molecular signatures database) collections--and 19 edge types from high-throughput publicly-available resources. From this network composed of 40,343 nodes and 1,608,168 edges, we extracted features that describe the topology between specific genes and diseases. Next, we trained a model from GWAS associations and predicted the probability of association between each protein-coding gene and each of 29 well-studied complex diseases. The model, which achieved 132-fold enrichment in precision at 10% recall, outperformed any individual domain, highlighting the benefit of integrative approaches. We identified pleiotropy, transcriptional signatures of perturbations, pathways, and protein interactions as influential mechanisms explaining pathogenesis. Our method successfully predicted the results (with AUROC = 0.79) from a withheld multiple sclerosis (MS) GWAS despite starting with only 13 previously associated genes. Finally, we combined our network predictions with statistical evidence of association to propose four novel MS genes, three of which (JAK2, REL, RUNX3) validated on the masked GWAS. Furthermore, our predictions provide biological support highlighting REL as the causal gene within its gene-rich locus. Users can browse all predictions online (http://het.io). Heterogeneous network edge prediction effectively prioritized genetic associations and provides a powerful new approach for data integration across multiple domains.

Dataset Information

Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network.

Publications

Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network.

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