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Genetic analysis of genome-wide variation in human gene expression

Author

Listed:
  • Michael Morley

    (University of Pennsylvania
    The Children's Hospital of Philadelphia)

  • Cliona M. Molony

    (University of Pennsylvania)

  • Teresa M. Weber

    (University of Pennsylvania
    The Children's Hospital of Philadelphia)

  • James L. Devlin

    (University of Pennsylvania)

  • Kathryn G. Ewens

    (University of Pennsylvania)

  • Richard S. Spielman

    (University of Pennsylvania)

  • Vivian G. Cheung

    (University of Pennsylvania
    University of Pennsylvania
    The Children's Hospital of Philadelphia)

Abstract

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:430:y:2004:i:7001:d:10.1038_nature02797
    DOI: 10.1038/nature02797
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    Cited by:

    1. Urmo Võsa & Tõnu Esko & Silva Kasela & Tarmo Annilo, 2015. "Altered Gene Expression Associated with microRNA Binding Site Polymorphisms," PLOS ONE, Public Library of Science, vol. 10(10), pages 1-24, October.
    2. Oualkacha Karim & Labbe Aurelie & Ciampi Antonio & Roy Marc-Andre & Maziade Michel, 2012. "Principal Components of Heritability for High Dimension Quantitative Traits and General Pedigrees," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(2), pages 1-27, January.
    3. Enrico Petretto & Leonardo Bottolo & Sarah R Langley & Matthias Heinig & Chris McDermott-Roe & Rizwan Sarwar & Michal Pravenec & Norbert Hübner & Timothy J Aitman & Stuart A Cook & Sylvia Richardson, 2010. "New Insights into the Genetic Control of Gene Expression using a Bayesian Multi-tissue Approach," PLOS Computational Biology, Public Library of Science, vol. 6(4), pages 1-13, April.
    4. Julia Schröder & Vitalia Schüller & Andrea May & Christian Gerges & Mario Anders & Jessica Becker & Timo Hess & Nicole Kreuser & René Thieme & Kerstin U Ludwig & Tania Noder & Marino Venerito & Lothar, 2019. "Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with gen," PLOS ONE, Public Library of Science, vol. 14(12), pages 1-12, December.
    5. Yixin Fang & Yang Feng & Ming Yuan, 2014. "Regularized principal components of heritability," Computational Statistics, Springer, vol. 29(3), pages 455-465, June.
    6. 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.
    7. Leopold Parts & Oliver Stegle & John Winn & Richard Durbin, 2011. "Joint Genetic Analysis of Gene Expression Data with Inferred Cellular Phenotypes," PLOS Genetics, Public Library of Science, vol. 7(1), pages 1-10, January.
    8. Witten Daniela M & Tibshirani Robert J., 2009. "Extensions of Sparse Canonical Correlation Analysis with Applications to Genomic Data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 8(1), pages 1-29, June.
    9. Bergersen Linn Cecilie & Glad Ingrid K. & Lyng Heidi, 2011. "Weighted Lasso with Data Integration," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 10(1), pages 1-29, August.
    10. Barbara E Stranger & Stephen B Montgomery & Antigone S Dimas & Leopold Parts & Oliver Stegle & Catherine E Ingle & Magda Sekowska & George Davey Smith & David Evans & Maria Gutierrez-Arcelus & Alkes P, 2012. "Patterns of Cis Regulatory Variation in Diverse Human Populations," PLOS Genetics, Public Library of Science, vol. 8(4), pages 1-13, April.
    11. Lingxue Zhang & Seyoung Kim, 2014. "Learning Gene Networks under SNP Perturbations Using eQTL Datasets," PLOS Computational Biology, Public Library of Science, vol. 10(2), pages 1-20, February.
    12. Eric R Gamazon & Hae-Kyung Im & Shiwei Duan & Yves A Lussier & Nancy J Cox & M Eileen Dolan & Wei Zhang, 2010. "ExprTarget: An Integrative Approach to Predicting Human MicroRNA Targets," PLOS ONE, Public Library of Science, vol. 5(10), pages 1-8, October.
    13. Ning Jiang & Minghui Wang & Tianye Jia & Lin Wang & Lindsey Leach & Christine Hackett & David Marshall & Zewei Luo, 2011. "A Robust Statistical Method for Association-Based eQTL Analysis," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-11, August.
    14. 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.
    15. Paul C Boutros & Ivy D Moffat & Allan B Okey & Raimo Pohjanvirta, 2011. "mRNA Levels in Control Rat Liver Display Strain-Specific, Hereditary, and AHR-Dependent Components," PLOS ONE, Public Library of Science, vol. 6(7), pages 1-15, July.
    16. 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.
    17. Mitsutaka Kadota & Howard H Yang & Nan Hu & Chaoyu Wang & Ying Hu & Philip R Taylor & Kenneth H Buetow & Maxwell P Lee, 2007. "Allele-Specific Chromatin Immunoprecipitation Studies Show Genetic Influence on Chromatin State in Human Genome," PLOS Genetics, Public Library of Science, vol. 3(5), pages 1-11, May.
    18. Bo Jiang & Jun S. Liu, 2015. "Bayesian Partition Models for Identifying Expression Quantitative Trait Loci," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 110(512), pages 1350-1361, December.
    19. 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.
    20. Xiaohong Li & Steven G Self & Patricia C Galipeau & Thomas G Paulson & Brian J Reid, 2007. "Direct Inference of SNP Heterozygosity Rates and Resolution of LOH Detection," PLOS Computational Biology, Public Library of Science, vol. 3(11), pages 1-10, November.
    21. Parkhomenko Elena & Tritchler David & Beyene Joseph, 2009. "Sparse Canonical Correlation Analysis with Application to Genomic Data Integration," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 8(1), pages 1-36, January.
    22. Cipolli III, William & Hanson, Timothy & McLain, Alexander C., 2016. "Bayesian nonparametric multiple testing," Computational Statistics & Data Analysis, Elsevier, vol. 101(C), pages 64-79.

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