Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

Abstract

Asthma is caused by a combination of poorly understood genetic and environmental factors1,2. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum3. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

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Figure 1: Study design.
Figure 2: Genome-wide association of 317,447 SNPs and asthma in 994 asthmatic children and 1,243 non-asthmatic children.
Figure 3: Association to asthma and transcript abundances of ORMDL3 on chromosome 17q21.

References

  1. 1

    Cookson, W. The immunogenetics of asthma and eczema: a new focus on the epithelium. Nature Rev. Immunol. 4, 978–988 (2004)

    CAS  Article  Google Scholar 

  2. 2

    Ober, C. & Hoffjan, S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun. 7, 95–100 (2006)

    CAS  Article  Google Scholar 

  3. 3

    Hjelmqvist, L. et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol. 3, RESEARCH0027 (2002)

    Article  Google Scholar 

  4. 4

    Weiland, S. K. et al. Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods. Eur. Respir. J. 24, 406–412 (2004)

    CAS  Article  Google Scholar 

  5. 5

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

    MathSciNet  MATH  Google Scholar 

  6. 6

    Setakis, E., Stirnadel, H. & Balding, D. J. Logistic regression protects against population structure in genetic association studies. Genome Res. 16, 290–296 (2006)

    CAS  Article  Google Scholar 

  7. 7

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

    ADS  CAS  Article  Google Scholar 

  8. 8

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

    ADS  CAS  Article  Google Scholar 

  9. 9

    Standards . for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am. Rev. Respir. Dis. 136, 225–244 (1987)

    Article  Google Scholar 

  10. 10

    British . guideline on the management of asthma. Thorax 58 (Suppl 1). i1–i94 (2003)

    Article  Google Scholar 

  11. 11

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

    Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

    Buetow, K. H. et al. High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc. Natl Acad. Sci. USA 98, 581–584 (2001)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Williams, R. L. A note on robust variance estimation for cluster-correlated data. Biometrics 56, 645–646 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Clayton, D. A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am. J. Hum. Genet. 65, 1170–1177 (1999)

    CAS  Article  Google Scholar 

  17. 17

    Storey, J. D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl Acad. Sci. USA 100, 9440–9445 (2003)

    ADS  MathSciNet  CAS  Article  Google Scholar 

  18. 18

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

    Article  Google Scholar 

  19. 19

    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  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Burdick, J. T., Chen, W. M., Abecasis, G. R. & Cheung, V. G. In silico method for inferring genotypes in pedigrees. Nature Genet. 38, 1002–1004 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Abecasis, G. R. & Cookson, W. O. GOLD–graphical overview of linkage disequilibrium. Bioinformatics 16, 182–183 (2000)

    CAS  Article  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, the German Ministry of education and research (BMBF), the national genome research network (NGFN), the National Institutes of Health (NHGRI and NHLBI; G.R.A.), and the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community). We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council and the Wellcome Trust. We thank J. Todd for genotyping rs3894194 in the 1958 British Birth cohort.

Microarray and chromosome 17 genotyping data have been deposited in the GEO database, with accession number GSE8052.

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Correspondence to William O. C. Cookson.

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This file contains Supplementary Tables 1-4 and Supplementary Figures 1-2 with Legends (PDF 141 kb)

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Moffatt, M., Kabesch, M., Liang, L. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007). https://doi.org/10.1038/nature06014

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