Predicting disease genes using protein-protein interactions. J Med Genet

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands
Journal of Medical Genetics (Impact Factor: 6.34). 09/2006; 43(8):691-8. DOI: 10.1136/jmg.2006.041376
Source: PubMed


The responsible genes have not yet been identified for many genetically mapped disease loci. Physically interacting proteins tend to be involved in the same cellular process, and mutations in their genes may lead to similar disease phenotypes.
To investigate whether protein-protein interactions can predict genes for genetically heterogeneous diseases.
72,940 protein-protein interactions between 10,894 human proteins were used to search 432 loci for candidate disease genes representing 383 genetically heterogeneous hereditary diseases. For each disease, the protein interaction partners of its known causative genes were compared with the disease associated loci lacking identified causative genes. Interaction partners located within such loci were considered candidate disease gene predictions. Prediction accuracy was tested using a benchmark set of known disease genes.
Almost 300 candidate disease gene predictions were made. Some of these have since been confirmed. On average, 10% or more are expected to be genuine disease genes, representing a 10-fold enrichment compared with positional information only. Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci.
Exploiting protein-protein interactions can greatly increase the likelihood of finding positional candidate disease genes. When applied on a large scale they can lead to novel candidate gene predictions.

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Available from: Berend Snel
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    • "Different approaches have used various data sources such as gene expression [2] [3], sequence similarity of genes, DNA methylation [4], tissue-specific information [5], functional similarity and annotations [2] [6], and protein-protein interactions (PPIs) [7] [8] in determining the strength of association between genes and diseases as well as associations between diseases and protein complexes [9]. Network-based prioritization methods [10] are based on the observation that genes related to similar diseases tend to lie close to one another in the PPI network [11]. Furthermore, some other researchers have considered phenotype similarity in terms of gene closeness to prioritize disease genes. "
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    ABSTRACT: Predicting disease genes for a particular genetic disease is very challenging in bioinformatics. Based on current research studies, this challenge can be tackled via network-based approaches. Furthermore, it has been highlighted that it is necessary to consider disease similarity along with the protein's proximity to disease genes in a protein-protein interaction (PPI) network in order to improve the accuracy of disease gene prioritization. In this study we propose a new algorithm called proximity disease similarity algorithm (ProSim), which takes both of the aforementioned properties into consideration, to prioritize disease genes. To illustrate the proposed algorithm, we have conducted six case studies, namely, prostate cancer, Alzheimer's disease, diabetes mellitus type 2, breast cancer, colorectal cancer, and lung cancer. We employed leave-one-out cross validation, mean enrichment, tenfold cross validation, and ROC curves to evaluate our proposed method and other existing methods. The results show that our proposed method outperforms existing methods such as PRINCE, RWR, and DADA.
    Full-text · Article · Sep 2015
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    • "Mimminer[39],[9]). Protein-protein interaction networks (PPI) are networks representing physical interactions between proteins; this is one of the strongest and most frequently used and powerful types of evidence for disease gene prediction[27](see also[13],[45],[29],[17],[44],[20],[40],[7],[23]). Gene expression information is one of the least biased pieces of evidence provided by high-throughput experiments[31]. "
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    ABSTRACT: Understanding the relationship between genetic diseases and the genes associated with them is an important problem regarding human health. The vast amount of data created from a large number of high-throughput experiments performed in the last few years has resulted in an unprecedented growth in computational methods to tackle the disease-gene association problem. Nowadays, it is clear that many of genetic diseases are not consequence of defects in a single gene. Instead, the disease phenotype is a reflection of various genetic components interacting in a complex network. In fact, most of genetic diseases occur as a result of various genes working in sync with each other in a single or several biological module (s). Using a genetic algorithm, we have devised a computational approach for disease-gene association. As a proof of concept, we apply this method to the problem of identifying genes involved in breast cancer.
    Full-text · Conference Paper · Nov 2014
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    • "Molecular networks, particularly protein-protein interaction networks (PIN), are extraordinarily informative because it is well-known that most cellular components do not solely perform the biological functionality, but interplay with other cellular components in an intricate interaction network [4-8]. Human PIN has been a valuable data resource to study molecular pathogenesis for a wide range of diseases [6-13]. Among those, numerous studies have been carried out to deeply understand the molecular networks related to neurodegenerative diseases (NDs), proposing different methodological approaches including network analysis to study Alzheimer’s disease based on PIN and data integration [14], inference of overlapping regulators of NDs in different organisms [15], pathway-based method to uncover the direct commonality among NDs [16], or reconstruction of NDs network based on PPI networks, regulatory networks, and Boolean networks [17]. "
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    ABSTRACT: Background Neurodegenerative dementia comprises chronic and progressive illnesses with major clinical features represented by progressive and permanent loss of cognitive and mental performance, including impairment of memory and brain functions. Many different forms of neurodegenerative dementia exist, but they are all characterized by death of specific subpopulation of neurons and accumulation of proteins in the brain. We incorporated data from OMIM and primary molecular targets of drugs in the different phases of the drug discovery process to try to reveal possible hidden mechanism in neurodegenerative dementia. In the present study, a systems biology approach was used to investigate the molecular connections among seemingly distinct complex diseases with the shared clinical symptoms of dementia that could suggest related disease mechanisms. Results Network analysis was applied to characterize an interaction network of disease proteins and drug targets, revealing a major role of metabolism and, predominantly, of autophagy process in dementia and, particularly, in tauopathies. Different phases of the autophagy molecular pathway appear to be implicated in the individual disease pathophysiology and specific drug targets associated to autophagy modulation could be considered for pharmacological intervention. In particular, in view of their centrality and of the direct association to autophagy proteins in the network, PP2A subunits could be suggested as a suitable molecular target for the development of novel drugs. Conclusion The present systems biology investigation identifies the autophagy pathway as a central dis-regulated process in neurodegenerative dementia with a prevalent involvement in diseases characterized by tau inclusion and indicates the disease-specific molecules in the pathway that could be considered for therapy.
    Full-text · Article · Jun 2014 · BMC Systems Biology
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