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Identifying the Genetic Variation of Gene Expression Using Gene Sets: Application of Novel Gene Set eQTL Approach to PharmGKB and KEGG

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  • Ryan Abo
  • Gregory D Jenkins
  • Liewei Wang
  • Brooke L Fridley

Abstract

Genetic variation underlying the regulation of mRNA gene expression in humans may provide key insights into the molecular mechanisms of human traits and complex diseases. Current statistical methods to map genetic variation associated with mRNA gene expression have typically applied standard linkage and/or association methods; however, when genome-wide SNP and mRNA expression data are available performing all pair wise comparisons is computationally burdensome and may not provide optimal power to detect associations. Consideration of different approaches to account for the high dimensionality and multiple testing issues may provide increased efficiency and statistical power. Here we present a novel approach to model and test the association between genetic variation and mRNA gene expression levels in the context of gene sets (GSs) and pathways, referred to as gene set – expression quantitative trait loci analysis (GS-eQTL). The method uses GSs to initially group SNPs and mRNA expression, followed by the application of principal components analysis (PCA) to collapse the variation and reduce the dimensionality within the GSs. We applied GS-eQTL to assess the association between SNP and mRNA expression level data collected from a cell-based model system using PharmGKB and KEGG defined GSs. We observed a large number of significant GS-eQTL associations, in which the most significant associations arose between genetic variation and mRNA expression from the same GS. However, a number of associations involving genetic variation and mRNA expression from different GSs were also identified. Our proposed GS-eQTL method effectively addresses the multiple testing limitations in eQTL studies and provides biological context for SNP-expression associations.

Suggested Citation

  • Ryan Abo & Gregory D Jenkins & Liewei Wang & Brooke L Fridley, 2012. "Identifying the Genetic Variation of Gene Expression Using Gene Sets: Application of Novel Gene Set eQTL Approach to PharmGKB and KEGG," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-11, August.
  • Handle: RePEc:plo:pone00:0043301
    DOI: 10.1371/journal.pone.0043301
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    References listed on IDEAS

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    1. Vivian G. Cheung & Richard S. Spielman & Kathryn G. Ewens & Teresa M. Weber & Michael Morley & Joshua T. Burdick, 2005. "Mapping determinants of human gene expression by regional and genome-wide association," Nature, Nature, vol. 437(7063), pages 1365-1369, October.
    2. Miriam F. Moffatt & Michael Kabesch & Liming Liang & Anna L. Dixon & David Strachan & Simon Heath & Martin Depner & Andrea von Berg & Albrecht Bufe & Ernst Rietschel & Andrea Heinzmann & Burkard Simma, 2007. "Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma," Nature, Nature, vol. 448(7152), pages 470-473, July.
    3. Zhijin Wu & Rafael A. Irizarry & Robert Gentleman & Francisco Martinez-Murillo & Forrest Spencer, 2004. "A Model-Based Background Adjustment for Oligonucleotide Expression Arrays," Journal of the American Statistical Association, American Statistical Association, vol. 99, pages 909-917, December.
    4. Zhijin Wu & Rafael Irizarry & Robert Gentleman & Francisco Martinez Murillo & Forrest Spencer, 2004. "A Model Based Background Adjustment for Oligonucleotide Expression Arrays," Johns Hopkins University Dept. of Biostatistics Working Paper Series 1001, Berkeley Electronic Press.
    5. Michael Morley & Cliona M. Molony & Teresa M. Weber & James L. Devlin & Kathryn G. Ewens & Richard S. Spielman & Vivian G. Cheung, 2004. "Genetic analysis of genome-wide variation in human gene expression," Nature, Nature, vol. 430(7001), pages 743-747, August.
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