Dataset Information

Predicting Type 1 Diabetes Candidate Genes using Human Protein-Protein Interaction Networks.

ABSTRACT: BACKGROUND: Proteins directly interacting with each other tend to have similar functions and be involved in the same cellular processes. Mutations in genes that code for them often lead to the same family of disease phenotypes. Efforts have been made to prioritize positional candidate genes for complex diseases utilize the protein-protein interaction (PPI) information. But such an approach is often considered too general to be practically useful for specific diseases. RESULTS: In this study we investigate the efficacy of this approach in type 1 diabetes (T1D). 266 known disease genes, and 983 positional candidate genes from the 18 established linkage loci of T1D, are compiled from the T1Dbase (http://t1dbase.org). We found that the PPI network of known T1D genes has distinct topological features from others, with significantly higher number of interactions among themselves even after adjusting for their high network degrees (p<1e-5). We then define those positional candidates that are first degree PPI neighbours of the 266 known disease genes to be new candidate disease genes. This leads to a list of 68 genes for further study. Cross validation using the known disease genes as benchmark reveals that the enrichment is ~17.1 fold over random selection, and ~4 fold better than using the linkage information alone. We find that the citations of the new candidates in T1D-related publications are significantly (p<1e-7) more than random, even after excluding the co-citation with the known disease genes; they are significantly over-represented (p<1e-10) in the top 30 GO terms shared by known disease genes. Furthermore, sequence analysis reveals that they contain significantly (p<0.0004) more protein domains that are known to be relevant to T1D. These findings provide indirect validation of the newly predicted candidates. CONCLUSION: Our study demonstrates the potential of the PPI information in prioritizing positional candidate genes for T1D.

SUBMITTER: Gao S

PROVIDER: S-EPMC2818071 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Predicting Type 1 Diabetes Candidate Genes using Human Protein-Protein Interaction Networks.

Gao Shouguo S Wang Xujing X

Journal of computer science and systems biology 20090401

BACKGROUND: Proteins directly interacting with each other tend to have similar functions and be involved in the same cellular processes. Mutations in genes that code for them often lead to the same family of disease phenotypes. Efforts have been made to prioritize positional candidate genes for complex diseases utilize the protein-protein interaction (PPI) information. But such an approach is often considered too general to be practically useful for specific diseases. RESULTS: In this study we i ...[more]

PMID: 20148193

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Project description:BackgroundDiabetes mellitus characterized by hyperglycemia as a result of insufficient production of or reduced sensitivity to insulin poses a growing threat to the health of people. It is a heterogeneous disorder with multiple etiologies consisting of type 1 diabetes, type 2 diabetes, gestational diabetes and so on. Diabetes-associated protein/gene prediction is a key step to understand the cellular mechanisms related to diabetes mellitus. Compared with experimental methods, computational predictions of candidate proteins/genes are cheaper and more effortless. Protein-protein interaction (PPI) data produced by the high-throughput technology have been used to prioritize candidate disease genes/proteins. However, the false interactions in the PPI data seriously hurt computational methods performance. In order to address that particular question, new methods are developed to identify candidate disease genes/proteins via integrating biological data from other sources.ResultsIn this study, a new framework called PDMG is proposed to predict candidate disease genes/proteins. First, the weighted networks are building in terms of the combination of the subcellular localization information and PPI data. To form the weighted networks, the importance of each compartment is evaluated based on the number of interacted proteins in this compartment. This is because the very different roles played by different compartments in cell activities. Besides, some compartments are more important than others. Based on the evaluated compartments, the interactions between proteins are scored and the weighted PPI networks are constructed. Second, the known disease genes are extracted from OMIM database as the seed genes to expand disease-specific networks based on the weighted networks. Third, the weighted values between a protein and its neighbors in the disease-related networks are added together and the sum is as the score of the protein. Last but not least, the proteins are ranked based on descending order of their scores. The candidate proteins in the top are considered to be associated with the diseases and are potential disease-related proteins. Various types of data, such as type 2 diabetes-associated genes, subcellular localizations and protein interactions, are used to test PDMG method.ConclusionsThe results show that the proteins/genes functionally exerting a direct influence over diabetes are consistently placed at the head of the queue. PDMG expands and ranks 445 candidate proteins from the seed set including original 27 type 2 diabetes proteins. Out of the top 27 proteins, 14 proteins are the real type 2 diabetes proteins. The literature extracted from the PubMed database has proved that, out of 13 novel proteins, 8 proteins are associated with diabetes.

Project description:BackgroundMultiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches.ResultsHere we report on a meta-analysis approach that integrates data of heterogeneous origin in the domain of type-2 diabetes mellitus (T2DM). Different data sources such as DNA microarrays and, complementing, qualitative data covering several human and mouse tissues are integrated and analyzed with a Bootstrap scoring approach in order to extract disease relevance of the genes. The purpose of the meta-analysis is two-fold: on the one hand it identifies a group of genes with overall disease relevance indicating common, tissue-independent processes related to the disease; on the other hand it identifies genes showing specific alterations with respect to a single study. Using a random sampling approach we computed a core set of 213 T2DM genes across multiple tissues in human and mouse, including well-known genes such as Pdk4, Adipoq, Scd, Pik3r1, Socs2 that monitor important hallmarks of T2DM, for example the strong relationship between obesity and insulin resistance, as well as a large fraction (128) of yet barely characterized novel candidate genes. Furthermore, we explored functional information and identified cellular networks associated with this core set of genes such as pathway information, protein-protein interactions and gene regulatory networks. Additionally, we set up a web interface in order to allow users to screen T2DM relevance for any - yet non-associated - gene.ConclusionIn our paper we have identified a core set of 213 T2DM candidate genes by a meta-analysis of existing data sources. We have explored the relation of these genes to disease relevant information and - using enrichment analysis - we have identified biological networks on different layers of cellular information such as signaling and metabolic pathways, gene regulatory networks and protein-protein interactions. The web interface is accessible via http://t2dm-geneminer.molgen.mpg.de.

Dataset Information

Predicting Type 1 Diabetes Candidate Genes using Human Protein-Protein Interaction Networks.

Publications

Predicting Type 1 Diabetes Candidate Genes using Human Protein-Protein Interaction Networks.

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