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Prioritizing causal disease genes using unbiased genomic features.

ABSTRACT: Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits.To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM.Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature.

SUBMITTER: Deo RC

PROVIDER: S-EPMC4279789 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Prioritizing causal disease genes using unbiased genomic features.

Deo Rahul C RC Musso Gabriel G Tasan Murat M Tang Paul P Poon Annie A Yuan Christiana C Felix Janine F JF Vasan Ramachandran S RS Beroukhim Rameen R De Marco Teresa T Kwok Pui-Yan PY MacRae Calum A CA Roth Frederick P FP

Genome biology 20141203 12

<h4>Background</h4>Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits.<h4>Results</h4>To aid in localizing causal gene ...[more]

PMID: 25633252

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Project description:Prioritizing disease genes is trying to identify potential disease causing genes for a given phenotype, which can be applied to reveal the inherited basis of human diseases and facilitate drug development. Our motivation is inspired by label propagation algorithm and the false positive protein-protein interactions that exist in the dataset. To the best of our knowledge, the false positive protein-protein interactions have not been considered before in disease gene prioritization. Label propagation has been successfully applied to prioritize disease causing genes in previous network-based methods. These network-based methods use basic label propagation, i.e. random walk, on networks to prioritize disease genes in different ways. However, all these methods can not deal with the situation in which plenty false positive protein-protein interactions exist in the dataset, because the PPI network is used as a fixed input in previous methods. This important characteristic of data source may cause a large deviation in results.A novel network-based framework IDLP is proposed to prioritize candidate disease genes. IDLP effectively propagates labels throughout the PPI network and the phenotype similarity network. It avoids the method falling when few disease genes are known. Meanwhile, IDLP models the bias caused by false positive protein interactions and other potential factors by treating the PPI network matrix and the phenotype similarity matrix as the matrices to be learnt. By amending the noises in training matrices, it improves the performance results significantly. We conduct extensive experiments over OMIM datasets, and IDLP has demonstrated its effectiveness compared with eight state-of-the-art approaches. The robustness of IDLP is also validated by doing experiments with disturbed PPI network. Furthermore, We search the literatures to verify the predicted new genes got by IDLP are associated with the given diseases, the high prediction accuracy shows IDLP can be a powerful tool to help biologists discover new disease genes.IDLP model is an effective method for disease gene prioritization, particularly for querying phenotypes without known associated genes, which would be greatly helpful for identifying disease genes for less studied phenotypes.https://github.com/nkiip/IDLP.

Project description:Despite important advances from Genome Wide Association Studies (GWAS), for most complex human traits and diseases, a sizable proportion of genetic variance remains unexplained and prediction accuracy (PA) is usually low. Evidence suggests that PA can be improved using Whole-Genome Regression (WGR) models where phenotypes are regressed on hundreds of thousands of variants simultaneously. The Genomic Best Linear Unbiased Prediction (G-BLUP, a ridge-regression type method) is a commonly used WGR method and has shown good predictive performance when applied to plant and animal breeding populations. However, breeding and human populations differ greatly in a number of factors that can affect the predictive performance of G-BLUP. Using theory, simulations, and real data analysis, we study the performance of G-BLUP when applied to data from related and unrelated human subjects. Under perfect linkage disequilibrium (LD) between markers and QTL, the prediction R-squared (R(2)) of G-BLUP reaches trait-heritability, asymptotically. However, under imperfect LD between markers and QTL, prediction R(2) based on G-BLUP has a much lower upper bound. We show that the minimum decrease in prediction accuracy caused by imperfect LD between markers and QTL is given by (1-b)(2), where b is the regression of marker-derived genomic relationships on those realized at causal loci. For pairs of related individuals, due to within-family disequilibrium, the patterns of realized genomic similarity are similar across the genome; therefore b is close to one inducing small decrease in R(2). However, with distantly related individuals b reaches very low values imposing a very low upper bound on prediction R(2). Our simulations suggest that for the analysis of data from unrelated individuals, the asymptotic upper bound on R(2) may be of the order of 20% of the trait heritability. We show how PA can be enhanced with use of variable selection or differential shrinkage of estimates of marker effects.

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Prioritizing causal disease genes using unbiased genomic features.

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Prioritizing causal disease genes using unbiased genomic features.

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