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More powerful genetic association testing via a new statistical framework for integrative genomics.

ABSTRACT: Integrative genomics offers a promising approach to more powerful genetic association studies. The hope is that combining outcome and genotype data with other types of genomic information can lead to more powerful SNP detection. We present a new association test based on a statistical model that explicitly assumes that genetic variations affect the outcome through perturbing gene expression levels. It is shown analytically that the proposed approach can have more power to detect SNPs that are associated with the outcome through transcriptional regulation, compared to tests using the outcome and genotype data alone, and simulations show that our method is relatively robust to misspecification. We also provide a strategy for applying our approach to high-dimensional genomic data. We use this strategy to identify a potentially new association between a SNP and a yeast cell's response to the natural product tomatidine, which standard association analysis did not detect.

SUBMITTER: Zhao SD

PROVIDER: S-EPMC4425276 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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More powerful genetic association testing via a new statistical framework for integrative genomics.

Zhao Sihai D SD Cai T Tony TT Li Hongzhe H

Biometrics 20140626 4

Integrative genomics offers a promising approach to more powerful genetic association studies. The hope is that combining outcome and genotype data with other types of genomic information can lead to more powerful SNP detection. We present a new association test based on a statistical model that explicitly assumes that genetic variations affect the outcome through perturbing gene expression levels. It is shown analytically that the proposed approach can have more power to detect SNPs that are as ...[more]

PMID: 24975802

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Project description:The widely used genetic pleiotropic analyses of multiple phenotypes are often designed for examining the relationship between common variants and a few phenotypes. They are not suited for both high dimensional phenotypes and high dimensional genotype (next-generation sequencing) data. To overcome limitations of the traditional genetic pleiotropic analysis of multiple phenotypes, we develop sparse structural equation models (SEMs) as a general framework for a new paradigm of genetic analysis of multiple phenotypes. To incorporate both common and rare variants into the analysis, we extend the traditional multivariate SEMs to sparse functional SEMs. To deal with high dimensional phenotype and genotype data, we employ functional data analysis and the alternative direction methods of multiplier (ADMM) techniques to reduce data dimension and improve computational efficiency.Using large scale simulations we showed that the proposed methods have higher power to detect true causal genetic pleiotropic structure than other existing methods. Simulations also demonstrate that the gene-based pleiotropic analysis has higher power than the single variant-based pleiotropic analysis. The proposed method is applied to exome sequence data from the NHLBI's Exome Sequencing Project (ESP) with 11 phenotypes, which identifies a network with 137 genes connected to 11 phenotypes and 341 edges. Among them, 114 genes showed pleiotropic genetic effects and 45 genes were reported to be associated with phenotypes in the analysis or other cardiovascular disease (CVD) related phenotypes in the literature.Our proposed sparse functional SEMs can incorporate both common and rare variants into the analysis and the ADMM algorithm can efficiently solve the penalized SEMs. Using this model we can jointly infer genetic architecture and casual phenotype network structure, and decompose the genetic effect into direct, indirect and total effect. Using large scale simulations we showed that the proposed methods have higher power to detect true causal genetic pleiotropic structure than other existing methods.

Dataset Information

More powerful genetic association testing via a new statistical framework for integrative genomics.

Publications

More powerful genetic association testing via a new statistical framework for integrative genomics.

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