Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Abstract

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Manhattan plot for the discovery genome-wide association meta-analysis.
Figure 2: Gene set enrichment map for the 11 significant gene sets from MAGENTA analysis.
Figure 3: Combined impact of risk alleles from the ten genome-wide significant loci on prevalence of allergic sensitization and allergic rhinitis (hay fever) in the population-based Health2006 replication study.

Accession codes

Accessions

ArrayExpress

Gene Expression Omnibus

References

  1. Johansson, S.G. et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 113, 832–836 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Anderson, G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107–1119 (2008).

    Article  PubMed  Google Scholar 

  3. Los, H., Postmus, P.E. & Boomsma, D.I. Asthma genetics and intermediate phenotypes: a review from twin studies. Twin Res. 4, 81–93 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Thomsen, S.F., Ulrik, C.S., Kyvik, K.O., Ferreira, M.A. & Backer, V. Multivariate genetic analysis of atopy phenotypes in a selected sample of twins. Clin. Exp. Allergy 36, 1382–1390 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Thomsen, S.F., van der Sluis, S., Kyvik, K.O. & Backer, V. A study of asthma severity in adult twins. Clin. Respir. J. 6, 228–237 (2012).

    Article  PubMed  Google Scholar 

  6. Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nat. Rev. Immunol. 8, 169–182 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Ramasamy, A. et al. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J. Allergy Clin. Immunol. 128, 996–1005 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Hinds, D.A. et al. A meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat. Genet. published online; 10.1035/ng.2686 (30 June 2013).

  9. Zeller, T. et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Adhikary, S. & Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nat. Rev. Mol. Cell Biol. 6, 635–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Huppi, K. et al. The identification of microRNAs in a genomically unstable region of human chromosome 8q24. Mol. Cancer Res. 6, 212–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Beck-Engeser, G.B. et al. Pvt1-encoded microRNAs in oncogenesis. Retrovirology 5, 4 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Esparza-Gordillo, J. et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat. Genet. 41, 596–601 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Ferreira, M.A. et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378, 1006–1014 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Anderson, C.A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246–252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kormann, M.S. et al. Toll-like receptor heterodimer variants protect from childhood asthma. J. Allergy Clin. Immunol. 122, 86–92 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Lazarus, R. et al. TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples. Am. J. Respir. Crit. Care Med. 170, 594–600 (2004).

    Article  PubMed  Google Scholar 

  20. Reijmerink, N.E. et al. Toll-like receptors and microbial exposure: gene-gene and gene-environment interaction in the development of atopy. Eur. Respir. J. 38, 833–840 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Tesse, R., Pandey, R.C. & Kabesch, M. Genetic variations in Toll-like receptor pathway genes influence asthma and atopy. Allergy 66, 307–316 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Potaczek, D.P. & Kabesch, M. Current concepts of IgE regulation and impact of genetic determinants. Clin. Exp. Allergy 42, 852–871 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Gudbjartsson, D.F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Savenije, O.E. et al. Interleukin-1 receptor–like 1 polymorphisms are associated with serum IL1RL1-a, eosinophils, and asthma in childhood. J. Allergy Clin. Immunol. 127, 750–756 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Ichii, H. et al. Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat. Immunol. 3, 558–563 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Christensen, U. et al. Family based association analysis of the IL2 and IL15 genes in allergic disorders. Eur. J. Hum. Genet. 14, 227–235 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Howell, W.M. & Holgate, S.T. HLA genetics and allergic disease. Thorax 50, 815–818 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Martin, A.M. et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc. Natl. Acad. Sci. USA 101, 4180–4185 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Strange, A. et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Segrè, A.V., Groop, L., Mootha, V.K., Daly, M.J. & Altshuler, D. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 6, e1001058 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Moffatt, M.F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Paternoster, L. et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat. Genet. 44, 187–192 (2012).

    Article  CAS  Google Scholar 

  35. Rabin, R.L. & Levinson, A.I. The nexus between atopic disease and autoimmunity: a review of the epidemiological and mechanistic literature. Clin. Exp. Immunol. 153, 19–30 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rathmann, W. et al. Incidence of type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4/F4 cohort study. Diabet. Med. 26, 1212–1219 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Mehta, D. et al. Impact of common regulatory single-nucleotide variants on gene expression profiles in whole blood. Eur. J. Hum. Genet. 21, 48–54 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    CAS  PubMed  Google Scholar 

  40. Fairfax, B.P. et al. Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles. Nat. Genet. 44, 502–510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Du, P., Kibbe, W.A. & Lin, S.M. lumi: a pipeline for processing Illumina microarray. Bioinformatics 24, 1547–1548 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Shabalin, A.A. Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics 28, 1353–1358 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Raychaudhuri, S. VIZ-GRAIL: visualizing functional connections across disease loci. Bioinformatics 27, 1589–1590 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A full list of acknowledgments for each study is given in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

Study-level data analysis: K.B., T.H.P. (meta-analysis and systems biology analyses), R. Granell (meta-analysis), D.P.S., A.C.A. (systems biology analyses), A.L., J.A.C., N.M.W., M.S., M. Kerkhof, B.K.B., M. Kaakinen, P. Sleimann, G.T., K. Schramm, E.K.-M., A.S., L.C., C.S.T., B.P.F., R. Gupta, M.B., S.W., H.H., D.S.P., A.C., G.H.K. and N.T. Study design: K.B., M.C.M., T.H.P., D.P.S., A.L., B.K.B., E.K.-M., A.S., C.F.R., G.W.M., S.C.D., P.E., M.J.A., J.C.K., R. Gupta, P.J.T., J.N.H., M.B., S.W., H.H., J. Heinrich, D.S.P., A.C., C.E.P., M.-R.J., G.H.K., N.T., M.A.F., H.B. and A.J.H. Writing manuscript: K.B., T.H.P., R. Granell, D.P.S., A.C.A., A.L., J.A.C., G.H.K., N.T., M.A.F., H.B. and A.J.H. Data collection: K.B., M.C.M., D.P.S., A.L., I.J., B.K.B., U.T., A.S., J. Hui, E.H.W., D.L.D., G.J., L.P., C.F.R., J.P., E.T., A.-L.H., S.C.D., L.L.H., C.H., A.J., B.P.F., J.C.K., M.J.A., P.J.T., P.H., P. Sly, M.B., H.H., K. Stefansson, J. Heinrich, D.S.P., A.C., M.-R.J., G.H.K., H.B. and A.J.H. Genotyping: K.B., A.L., J.A.C., I.J., P. Sleimann, U.T., S.B., E.K.-M., A.S., B.S.P., C.M.T.T., S.M.R., W.L.M., G.W.M., L.L.H., J.P.K., M.W., H.H., K. Stefansson, A.C., C.E.P., M.-R.J., G.H.K. and H.B. Revising and reviewing manuscript: K.B., M.C.M., T.H.P., R. Granell, D.P.S., A.C.A., A.L., J.A.C., N.M.W., M.S., M. Kerkhof, I.J., B.K.B., M. Kaakinen, P. Sleimann, G.T., U.T., K. Schramm, S.B., E.K.-M., A.S., B.S.P., L.C., J. Hui, E.H.W., C.M.T.T., D.L.D., G.J., S.M.R., W.L.M., L.P., C.F.R., J.P., C.S.T., E.T., G.W.M., A.-L.H., S.C.D., L.L.H., C.H., J.P.K., P.E., A.J., M.W., M.J.A., B.P.F., J.C.K., R. Gupta, P.J.T., P.H., P. Sly, J.N.H., M.B., S.W., H.H., K. Stefansson, J. Heinrich, D.S.P., A.C., C.E.P., M.-R.J., G.H.K., N.T., M.A.F., H.B. and A.J.H.

Corresponding author

Correspondence to Klaus Bønnelykke.

Ethics declarations

Competing interests

I.J., G.T., U.T. and K. Stefansson are employees of deCODE Genetics. The other authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1–5, Supplementary Tables 1–19 and Supplementary Note (PDF 3106 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bønnelykke, K., Matheson, M., Pers, T. et al. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nat Genet 45, 902–906 (2013). https://doi.org/10.1038/ng.2694

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2694

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing