Joint analysis of SNP and gene expression data in genetic association studies of complex diseases

DOI10.1214/13-AOAS690zbMATH Open1454.62343arXiv1404.6423OpenAlexW3098193298WikidataQ30800044 ScholiaQ30800044MaRDI QIDQ2453676FDOQ2453676

Authors: Yen-Tsung Huang, Tyler J. Vanderweele, Xihong Lin 

Publication date: 10 June 2014

Published in: The Annals of Applied Statistics (Search for Journal in Brave)

Abstract: Genetic association studies have been a popular approach for assessing the association between common Single Nucleotide Polymorphisms (SNPs) and complex diseases. However, other genomic data involved in the mechanism from SNPs to disease, for example, gene expressions, are usually neglected in these association studies. In this paper, we propose to exploit gene expression information to more powerfully test the association between SNPs and diseases by jointly modeling the relations among SNPs, gene expressions and diseases. We propose a variance component test for the total effect of SNPs and a gene expression on disease risk. We cast the test within the causal mediation analysis framework with the gene expression as a potential mediator. For eQTL SNPs, the use of gene expression information can enhance power to test for the total effect of a SNP-set, which is the combined direct and indirect effects of the SNPs mediated through the gene expression, on disease risk. We show that the test statistic under the null hypothesis follows a mixture of $ch{i}^2$ distributions, which can be evaluated analytically or empirically using the resampling-based perturbation method. We construct tests for each of three disease models that are determined by SNPs only, SNPs and gene expression, or include also their interactions. As the true disease model is unknown in practice, we further propose an omnibus test to accommodate different underlying disease models. We evaluate the finite sample performance of the proposed methods using simulation studies, and show that our proposed test performs well and the omnibus test can almost reach the optimal power where the disease model is known and correctly specified. We apply our method to reanalyze the overall effect of the SNP-set and expression of the ORMDL3 gene on the risk of asthma.

Full work available at URL: https://arxiv.org/abs/1404.6423

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zbMATH Keywords

causal inferencemixed modelsscore testmediation analysisdata intergrationSNP set analysisvariance component set

Mathematics Subject Classification ID

Applications of statistics to biology and medical sciences; meta analysis (62P10)

Cites Work

• Algorithm AS 155: The Distribution of a Linear Combination of χ 2 Random Variables
• A resampling method based on pivotal estimating functions
• Models for Longitudinal Data: A Generalized Estimating Equation Approach
• Variance component testing in generalised linear models with random effects
• A Direct Approach to False Discovery Rates
• Bayesian inference for causal effects: The role of randomization
• Identification, inference and sensitivity analysis for causal mediation effects
• A score based approach to wild bootstrap inference
• Conceptual issues concerning mediation, interventions and composition
• Title not available (Why is that?)
• Joint analysis of SNP and gene expression data in genetic association studies of complex diseases

Cited In (11)

• Bayesian approaches for large biological networks
• Joint analysis of SNP and gene expression data in genetic association studies of complex diseases
• Robust score tests with missing data in genomics studies
• Power of testing for exposure effects under incomplete mediation
• Hypothesis test of mediation effect in causal mediation model with high-dimensional continuous mediators
• Multiple testing approaches for hypotheses in integrative genomics
• Mediation analysis for common binary outcomes
• Modeling the Association Between Clusters of SNPs and Disease Responses
• Varying Coefficient Mediation Model and Application to Analysis of Behavioral Economics Data
• Modeling and testing for joint association using a genetic random field model
• Sufficient direction factor model and its application to gene expression quantitative trait loci discovery

Uses Software

• IMPUTE
• AS 155

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