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Sparse simultaneous signal detection for identifying genetically controlled disease genes.

ABSTRACT: Genome-wide association studies (GWAS) and differential expression analyses have had limited success in finding genes that cause complex diseases such as heart failure (HF), a leading cause of death in the United States. This paper proposes a new statistical approach that integrates GWAS and expression quantitative trait loci (eQTL) data to identify important HF genes. For such genes, genetic variations that perturb its expression are also likely to influence disease risk. The proposed method thus tests for the presence of simultaneous signals: SNPs that are associated with the gene's expression as well as with disease. An analytic expression for the p-value is obtained, and the method is shown to be asymptotically adaptively optimal under certain conditions. It also allows the GWAS and eQTL data to be collected from different groups of subjects, enabling investigators to integrate public resources with their own data. Simulation experiments show that it can be more powerful than standard approaches and also robust to linkage disequilibrium between variants. The method is applied to an extensive analysis of HF genomics and identifies several genes with biological evidence for being functionally relevant in the etiology of HF. It is implemented in the R package ssa.

SUBMITTER: Zhao SD

PROVIDER: S-EPMC5784841 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Sparse simultaneous signal detection for identifying genetically controlled disease genes.

Zhao Sihai Dave SD Cai T Tony TT Cappola Thomas P TP Margulies Kenneth B KB Li Hongzhe H

Journal of the American Statistical Association 20170105 519

Genome-wide association studies (GWAS) and differential expression analyses have had limited success in finding genes that cause complex diseases such as heart failure (HF), a leading cause of death in the United States. This paper proposes a new statistical approach that integrates GWAS and expression quantitative trait loci (eQTL) data to identify important HF genes. For such genes, genetic variations that perturb its expression are also likely to influence disease risk. The proposed method th ...[more]

PMID: 29375169

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Project description:BackgroundHigh throughput data are complex and methods that reveal structure underlying the data are most useful. Principal component analysis, frequently implemented as a singular value decomposition, is a popular technique in this respect. Nowadays often the challenge is to reveal structure in several sources of information (e.g., transcriptomics, proteomics) that are available for the same biological entities under study. Simultaneous component methods are most promising in this respect. However, the interpretation of the principal and simultaneous components is often daunting because contributions of each of the biomolecules (transcripts, proteins) have to be taken into account.ResultsWe propose a sparse simultaneous component method that makes many of the parameters redundant by shrinking them to zero. It includes principal component analysis, sparse principal component analysis, and ordinary simultaneous component analysis as special cases. Several penalties can be tuned that account in different ways for the block structure present in the integrated data. This yields known sparse approaches as the lasso, the ridge penalty, the elastic net, the group lasso, sparse group lasso, and elitist lasso. In addition, the algorithmic results can be easily transposed to the context of regression. Metabolomics data obtained with two measurement platforms for the same set of Escherichia coli samples are used to illustrate the proposed methodology and the properties of different penalties with respect to sparseness across and within data blocks.ConclusionSparse simultaneous component analysis is a useful method for data integration: First, simultaneous analyses of multiple blocks offer advantages over sequential and separate analyses and second, interpretation of the results is highly facilitated by their sparseness. The approach offered is flexible and allows to take the block structure in different ways into account. As such, structures can be found that are exclusively tied to one data platform (group lasso approach) as well as structures that involve all data platforms (Elitist lasso approach).AvailabilityThe additional file contains a MATLAB implementation of the sparse simultaneous component method.

Dataset Information

Sparse simultaneous signal detection for identifying genetically controlled disease genes.

Publications

Sparse simultaneous signal detection for identifying genetically controlled disease genes.

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