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Genetic analysis of genome-wide variation in human gene expression

Nature volume 430, pages 743–747 (2004)Cite this article

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.

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Figure 1: Genome scans for ten expression phenotypes.
Figure 2: Master transcriptional regulators.
Figure 3: Regression of expression phenotype of LOC64167 and HSD17B12 on nearby SNPs.

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Acknowledgements

We thank T. Matise and W. Ewens for discussions and advice, and J. Burdick for technical help. Some analyses for this paper were carried out by using the program package S.A.G.E., which is supported by a grant from the National Center for Research Resources. This work is supported by grants from the National Institutes of Health (to R.S.S. and V.G.C.) and the W.W. Smith Endowed Chair (to V.G.C.).

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Author notes

  1. Michael Morley and Cliona M. Molony: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pediatrics, University of Pennsylvania,

    Michael Morley, Teresa M. Weber & Vivian G. Cheung

  2. Department of Genetics, University of Pennsylvania,

    Cliona M. Molony, James L. Devlin, Kathryn G. Ewens, Richard S. Spielman & Vivian G. Cheung

  3. The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA

    Michael Morley, Teresa M. Weber & Vivian G. Cheung

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  1. Michael Morley
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Correspondence to Richard S. Spielman or Vivian G. Cheung.

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Morley, M., Molony, C., Weber, T. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004). https://doi.org/10.1038/nature02797

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