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Variations in DNA elucidate molecular networks that cause disease

Author

Listed:
  • Yanqing Chen

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Jun Zhu

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Pek Yee Lum

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Xia Yang

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Shirly Pinto

    (Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA)

  • Douglas J. MacNeil

    (Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA)

  • Chunsheng Zhang

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • John Lamb

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Stephen Edwards

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Solveig K. Sieberts

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Amy Leonardson

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Lawrence W. Castellini

    (Molecular Genetics, and Immunology)

  • Susanna Wang

    (Molecular Genetics, and Immunology)

  • Marie-France Champy

    (Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France)

  • Bin Zhang

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Valur Emilsson

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

  • Sudheer Doss

    (Molecular Genetics, and Immunology)

  • Anatole Ghazalpour

    (Molecular Genetics, and Immunology)

  • Steve Horvath

    (and)

  • Thomas A. Drake

    (UCLA, 650 Young Drive South, Los Angeles, California 90095, USA)

  • Aldons J. Lusis

    (Molecular Genetics, and Immunology
    and)

  • Eric E. Schadt

    (Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA)

Abstract

Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase β (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.

Suggested Citation

  • Yanqing Chen & Jun Zhu & Pek Yee Lum & Xia Yang & Shirly Pinto & Douglas J. MacNeil & Chunsheng Zhang & John Lamb & Stephen Edwards & Solveig K. Sieberts & Amy Leonardson & Lawrence W. Castellini & Su, 2008. "Variations in DNA elucidate molecular networks that cause disease," Nature, Nature, vol. 452(7186), pages 429-435, March.
    • Handle: RePEc:nat:nature:v:452:y:2008:i:7186:d:10.1038_nature06757
    DOI: 10.1038/nature06757
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    Cited by:

    1. Jin Hyun Ju & Sushila A Shenoy & Ronald G Crystal & Jason G Mezey, 2017. "An independent component analysis confounding factor correction framework for identifying broad impact expression quantitative trait loci," PLOS Computational Biology, Public Library of Science, vol. 13(5), pages 1-26, May.
    2. Benjamin A Logsdon & Jason Mezey, 2010. "Gene Expression Network Reconstruction by Convex Feature Selection when Incorporating Genetic Perturbations," PLOS Computational Biology, Public Library of Science, vol. 6(12), pages 1-13, December.
    3. Josine L Min & Jennifer M Taylor & J Brent Richards & Tim Watts & Fredrik H Pettersson & John Broxholme & Kourosh R Ahmadi & Gabriela L Surdulescu & Ernesto Lowy & Christian Gieger & Chris Newton-Cheh, 2011. "The Use of Genome-Wide eQTL Associations in Lymphoblastoid Cell Lines to Identify Novel Genetic Pathways Involved in Complex Traits," PLOS ONE, Public Library of Science, vol. 6(7), pages 1-14, July.
    4. Eric A Stone & Julien F Ayroles, 2009. "Modulated Modularity Clustering as an Exploratory Tool for Functional Genomic Inference," PLOS Genetics, Public Library of Science, vol. 5(5), pages 1-13, May.
    5. Wei Zhang & Jun Zhu & Eric E Schadt & Jun S Liu, 2010. "A Bayesian Partition Method for Detecting Pleiotropic and Epistatic eQTL Modules," PLOS Computational Biology, Public Library of Science, vol. 6(1), pages 1-10, January.
    6. Won Jun Lee & Sang Cheol Kim & Jung-Ho Yoon & Sang Jun Yoon & Johan Lim & You-Sun Kim & Sung Won Kwon & Jeong Hill Park, 2016. "Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set and Network Analysis," PLOS ONE, Public Library of Science, vol. 11(2), pages 1-20, February.
    7. Lina Zgaga & Felix Agakov & Evropi Theodoratou & Susan M Farrington & Albert Tenesa & Malcolm G Dunlop & Paul McKeigue & Harry Campbell, 2013. "Model Selection Approach Suggests Causal Association between 25-Hydroxyvitamin D and Colorectal Cancer," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-11, May.
    8. Michael J McGeachie & Hsun-Hsien Chang & Scott T Weiss, 2014. "CGBayesNets: Conditional Gaussian Bayesian Network Learning and Inference with Mixed Discrete and Continuous Data," PLOS Computational Biology, Public Library of Science, vol. 10(6), pages 1-7, June.
    9. Hui-Min Wang & Ching-Lin Hsiao & Ai-Ru Hsieh & Ying-Chao Lin & Cathy S J Fann, 2012. "Constructing Endophenotypes of Complex Diseases Using Non-Negative Matrix Factorization and Adjusted Rand Index," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-12, July.
    10. Oliver Stegle & Leopold Parts & Richard Durbin & John Winn, 2010. "A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-11, May.
    11. Valur Emilsson & Elias F. Gudmundsson & Thorarinn Jonmundsson & Brynjolfur G. Jonsson & Michael Twarog & Valborg Gudmundsdottir & Zhiguang Li & Nancy Finkel & Stephen Poor & Xin Liu & Robert Esterberg, 2022. "A proteogenomic signature of age-related macular degeneration in blood," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Eric P Xing & Ross E Curtis & Georg Schoenherr & Seunghak Lee & Junming Yin & Kriti Puniyani & Wei Wu & Peter Kinnaird, 2014. "GWAS in a Box: Statistical and Visual Analytics of Structured Associations via GenAMap," PLOS ONE, Public Library of Science, vol. 9(6), pages 1-19, June.
    13. Ville-Petteri Mäkinen & Mete Civelek & Qingying Meng & Bin Zhang & Jun Zhu & Candace Levian & Tianxiao Huan & Ayellet V Segrè & Sujoy Ghosh & Juan Vivar & Majid Nikpay & Alexandre F R Stewart & Christ, 2014. "Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease," PLOS Genetics, Public Library of Science, vol. 10(7), pages 1-14, July.
    14. Emma Pierson & the GTEx Consortium & Daphne Koller & Alexis Battle & Sara Mostafavi, 2015. "Sharing and Specificity of Co-expression Networks across 35 Human Tissues," PLOS Computational Biology, Public Library of Science, vol. 11(5), pages 1-19, May.
    15. Kai Wang & Manikandan Narayanan & Hua Zhong & Martin Tompa & Eric E Schadt & Jun Zhu, 2009. "Meta-analysis of Inter-species Liver Co-expression Networks Elucidates Traits Associated with Common Human Diseases," PLOS Computational Biology, Public Library of Science, vol. 5(12), pages 1-16, December.

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