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A genome-wide association study of global gene expression

Abstract

We have created a global map of the effects of polymorphism on gene expression in 400 children from families recruited through a proband with asthma. We genotyped 408,273 SNPs and identified expression quantitative trait loci from measurements of 54,675 transcripts representing 20,599 genes in Epstein-Barr virus–transformed lymphoblastoid cell lines. We found that 15,084 transcripts (28%) representing 6,660 genes had narrow-sense heritabilities (H2) > 0.3. We executed genome-wide association scans for these traits and found peak lod scores between 3.68 and 59.1. The most highly heritable traits were markedly enriched in Gene Ontology descriptors for response to unfolded protein (chaperonins and heat shock proteins), regulation of progression through the cell cycle, RNA processing, DNA repair, immune responses and apoptosis. SNPs that regulate expression of these genes are candidates in the study of degenerative diseases, malignancy, infection and inflammation. We have created a downloadable database to facilitate use of our findings in the mapping of complex disease loci.

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Figure 1: Summaries of heritability and association analysis for all genes.
Figure 2: Proportion of significantly associated SNPs and expression trait heritability.
Figure 3: Associations in cis and trans.
Figure 4: Regulators of genes involved in the cell cycle or immune response.

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Accessions

Gene Expression Omnibus

References

  1. 1

    Schadt, E.E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Moffatt, M.F. et al. Genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Nature 448, 470–473 (2007).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 58 (Suppl.), i1–i94 (2003).

  5. 5

    Abecasis, G.R., Cookson, W.O. & Cardon, L.R. Selection strategies for disequilibrium mapping of quantitative traits in nuclear families. Am. J. Hum. Genet. 65, A245 (1999).

    Google Scholar 

  6. 6

    Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).

    Article  PubMed  Google Scholar 

  7. 7

    Bolstad, B.M., Irizarry, R.A., Astrand, M. & Speed, T.P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Yan, H., Yuan, W., Velculescu, V.E., Vogelstein, B. & Kinzler, K.W. Allelic variation in human gene expression. Science 297, 1143 (2002).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Cheung, V.G. et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nat. Genet. 33, 422–425 (2003).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Chen, W.-M. & Abecasis, G.R. Family based association tests for genome wide association scans. Am. J. Hum. Genet. (in the press).

  12. 12

    Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Hubner, N. et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat. Genet. 37, 243–253 (2005).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Monks, S.A. et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Beaty, J.S., West, K.A. & Nepom, G.T. Functional effects of a natural polymorphism in the transcriptional regulatory sequence of HLA-DQB1. Mol. Cell. Biol. 15, 4771–4782 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Libioulle, C. et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007) (doi:10.1371/journal.pgen.0030058).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Thein, S.L. et al. Intergenic variants of HBS1L-MYB are responsible for a major QTL on chromosome 6q23 influencing HbF levels in adults. Proc. Natl. Acad. Sci. USA 104, 11346–11351 (2007).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Spielman, R.S. et al. Common genetic variants account for differences in gene expression among ethnic groups. Nat. Genet. 39, 226–231 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Gunderson, K.L., Steemers, F.J., Lee, G., Mendoza, L.G. & Chee, M.S. A genome-wide scalable SNP genotyping assay using microarray technology. Nat. Genet. 37, 549–554 (2005).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Steemers, F.J. et al. Whole-genome genotyping with the single-base extension assay. Nat. Methods 3, 31–33 (2006).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. Ser. B 57, 289–300 (1995).

    Google Scholar 

  25. 25

    Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Harris, M.A. et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res. 32, D258–D261 (2004).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The study was funded by the Wellcome Trust, the Medical Research Council, the French Ministry of Higher Education and Research and the US National Institutes of Health (the National Human Genome Research Institute and the National Heart, Lung and Blood Institute).

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Correspondence to William O C Cookson.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 (PDF 149 kb)

Supplementary Table 1

Transcripts and SNPs with H2>0.3 and LOD scores for association>6. (XLS 2671 kb)

Supplementary Table 2

Summary of sequential search for independent associations of SNPs with individual transcripts (XLS 55 kb)

Supplementary Table 3

Potential Master Regulators (XLS 456 kb)

Supplementary Table 4

Gene Ontology (Biological Process) analyses for most highly heritable traits (XLS 60 kb)

Supplementary Table 5

Lists of genes in the three most significant GO-BP classes (XLS 1059 kb)

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Dixon, A., Liang, L., Moffatt, M. et al. A genome-wide association study of global gene expression. Nat Genet 39, 1202–1207 (2007). https://doi.org/10.1038/ng2109

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