A genome-wide association study of global gene expression (original) (raw)

Nature Genetics volume 39, pages 1202–1207 (2007)Cite this article

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 (_H_2) > 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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Schadt, E.E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003).
    Article CAS PubMed Google Scholar
  2. Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).
    Article CAS PubMed PubMed Central Google Scholar
  3. Moffatt, M.F. et al. Genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Nature 448, 470–473 (2007).
    Article CAS PubMed Google Scholar
  4. British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 58 (Suppl.), i1–i94 (2003).
  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. 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. 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).
    Article CAS PubMed Google Scholar
  8. Yan, H., Yuan, W., Velculescu, V.E., Vogelstein, B. & Kinzler, K.W. Allelic variation in human gene expression. Science 297, 1143 (2002).
    Article CAS PubMed Google Scholar
  9. Cheung, V.G. et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nat. Genet. 33, 422–425 (2003).
    Article CAS PubMed Google Scholar
  10. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).
    Article CAS PubMed Google Scholar
  11. Chen, W.-M. & Abecasis, G.R. Family based association tests for genome wide association scans. Am. J. Hum. Genet. (in the press).
  12. Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).
    Article CAS PubMed Google Scholar
  13. Hubner, N. et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat. Genet. 37, 243–253 (2005).
    Article CAS PubMed Google Scholar
  14. Monks, S.A. et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).
    Article CAS PubMed PubMed Central Google Scholar
  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).
    Article CAS PubMed PubMed Central Google Scholar
  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).
    Article CAS PubMed PubMed Central Google Scholar
  17. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).
    Article CAS PubMed Google Scholar
  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).
    Article CAS PubMed Google Scholar
  19. Spielman, R.S. et al. Common genetic variants account for differences in gene expression among ethnic groups. Nat. Genet. 39, 226–231 (2007).
    Article CAS PubMed PubMed Central Google Scholar
  20. Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).
    Article CAS PubMed PubMed Central Google Scholar
  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).
    Article CAS PubMed Google Scholar
  22. Steemers, F.J. et al. Whole-genome genotyping with the single-base extension assay. Nat. Methods 3, 31–33 (2006).
    Article CAS PubMed Google Scholar
  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).
    Article CAS PubMed Google Scholar
  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. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
    Article CAS PubMed PubMed Central Google Scholar
  26. Harris, M.A. et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res. 32, D258–D261 (2004).
    Article CAS PubMed Google Scholar

Download references

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).

Author information

Author notes

  1. Anna L Dixon, Liming Liang and Miriam F Moffatt: These authors contributed equally to this work.

Authors and Affiliations

  1. National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK
    Anna L Dixon, Miriam F Moffatt, Kenny C C Wong & William O C Cookson
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
    Anna L Dixon, Jenny Taylor & Martin Farrall
  3. Department of Biostatistics, Center for Statistical Genetics, School of public Health, Ann Arbor, 48109-2029, Michigan, USA
    Liming Liang, Wei Chen & Gonçalo R Abecasis
  4. Centre National de Génotypage, Institut Génomique, Commissariat à l′Énergie Atomique, Evry, 91057, France
    Simon Heath, Ivo Gut & G Mark Lathrop
  5. European Collection of Cell Cultures (ECACC), Porton Down, SP4 0JG, UK
    Edward Burnett

Authors

  1. Anna L Dixon
    You can also search for this author inPubMed Google Scholar
  2. Liming Liang
    You can also search for this author inPubMed Google Scholar
  3. Miriam F Moffatt
    You can also search for this author inPubMed Google Scholar
  4. Wei Chen
    You can also search for this author inPubMed Google Scholar
  5. Simon Heath
    You can also search for this author inPubMed Google Scholar
  6. Kenny C C Wong
    You can also search for this author inPubMed Google Scholar
  7. Jenny Taylor
    You can also search for this author inPubMed Google Scholar
  8. Edward Burnett
    You can also search for this author inPubMed Google Scholar
  9. Ivo Gut
    You can also search for this author inPubMed Google Scholar
  10. Martin Farrall
    You can also search for this author inPubMed Google Scholar
  11. G Mark Lathrop
    You can also search for this author inPubMed Google Scholar
  12. Gonçalo R Abecasis
    You can also search for this author inPubMed Google Scholar
  13. William O C Cookson
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toWilliam O C Cookson.

Supplementary information

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by