Joint analysis of SNP and gene expression data in genetic association studies of complex diseases
Open accessAbstract
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 $\chi^{2}$ 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.
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Mediation analysis was developed to integrate SNP and gene expression data, treating gene expression as the mediator in the causal mechanism from SNPs to disease.
“For example, a regression-based method termed “mediation analysis” was developed to integrate SNP and gene expression data, treating the gene expression as the mediator in the causal mechanism from SNPs to disease [45, 46].”
From Multi-omics approaches to disease (2017) · cites this paper as [45]
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- Authors
- Huang, Y.-T., VanderWeele, T. J., & Lin, X.
- Affiliations
- Brown University (US)
- Harvard University (US)
- ORCID
- Lin, Xihong
- Venue
- The Annals of Applied Statistics
- Publisher
- Institute of Mathematical Statistics
- Published
- 2014-03-01
- Volume
- 8
- Issue
- 1
- Pages
- 352-376
- ISSN
- 1932-6157 (ISSN-L)
- 1941-7330
- PMC
- PMC3981558
- OpenAlex
- W1979676475
- Cited by
- 88
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 15 · 2018: 6 · 2017: 8 · 2016: 11 · 2015: 4 · 2014: 8
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Annals of Applied Statistics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- arXiv (Cornell University) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Project Euclid (Cornell University) (submittedVersion)
- arXiv (Cornell University)
- Funders
- National Cancer Institute (CA134294., R01CA076404, CA076404, R37CA076404, P01CA134294, R35CA197449)
- National Institute of Environmental Health Sciences (P42ES016454, P30ES000002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- single nucleotide polymorphisms, gene expression, genetic association, complex diseases, causal mediation analysis, expression quantitative trait loci, perturbation method, omnibus test, gene-environment interaction, asthma, ORMDL3
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