Letter

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology

Received:
Accepted:
Published online:

Abstract

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals1, partly because of a shared genetic origin2,3,4. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10−8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

  • Subscribe to Nature Genetics for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    et al. Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study. Lancet Respir. Med. 2, 131–140 (2014).

  2. 2.

    et al. Findings on the atopic triad from a Danish twin registry. Int. J. Tuberc. Lung Dis. 10, 1268–1272 (2006).

  3. 3.

    & Genetics of parentally reported asthma, eczema and rhinitis in 5-yr-old twins. Eur. Respir. J. 29, 516–521 (2007).

  4. 4.

    et al. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47, 1385–1392 (2015).

  5. 5.

    et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375, S1–S3 (2012).

  6. 6.

    Improving the power to detect risk variants for allergic disease by defining case–control status based on both asthma and hay fever. Twin Res. Hum. Genet. 17, 505–511 (2014).

  7. 7.

    et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

  8. 8.

    GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

  9. 9.

    et al. The anatomical distribution of genetic associations. Nucleic Acids Res. 43, 10804–10820 (2015).

  10. 10.

    et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).

  11. 11.

    et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

  12. 12.

    et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat. Genet. 47, 115–125 (2015).

  13. 13.

    , & Etiological relationships in atopy: a review of twin studies. Twin Res. Hum. Genet. 11, 112–120 (2008).

  14. 14.

    et al. Use of genome-wide association studies for drug repositioning. Nat. Biotechnol. 30, 317–320 (2012).

  15. 15.

    et al. Disease variants alter transcription factor levels and methylation of their binding sites. Nat. Genet. 49, 131–138 (2017).

  16. 16.

    et al. Epigenetic signatures of cigarette smoking. Circ Cardiovasc Genet 9, 436–447 (2016).

  17. 17.

    et al. Identification of a novel family of targets of PYK2 related to Drosophila retinal degeneration B (rdgB) protein. Mol. Cell. Biol. 19, 2278–2288 (1999).

  18. 18.

    & β2 integrin–dependent phosphorylation of protein-tyrosine kinase Pyk2 stimulated by tumor necrosis factor α and fMLP in human neutrophils adherent to fibrinogen. FEBS Lett. 451, 33–38 (1999).

  19. 19.

    , & Pyk2 is required for neutrophil degranulation and host defense responses to bacterial infection. J. Immunol. 186, 1656–1665 (2011).

  20. 20.

    , & METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

  21. 21.

    , , & The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. Eur. J. Hum. Genet. 24, 1202–1205 (2016).

  22. 22.

    et al. Allergic multimorbidity of asthma, rhinitis and eczema over 20 years in the German birth cohort MAS. Pediatr. Allergy Immunol. 26, 431–437 (2015).

  23. 23.

    , , , & Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy 70, 836–845 (2015).

  24. 24.

    et al. Identification of a new locus at 16q12 associated with time to asthma onset. J. Allergy Clin. Immunol. 138, 1071–1080 (2016).

  25. 25.

    et al. Atopic dermatitis and the atopic march revisited. Allergy 69, 17–27 (2014).

  26. 26.

    & wANNOVAR: annotating genetic variants for personal genomes via the web. J. Med. Genet. 49, 433–436 (2012).

  27. 27.

    1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  28. 28.

    , , & GeneCards: integrating information about genes, proteins and diseases. Trends Genet. 13, 163 (1997).

  29. 29.

    et al. An efficient multiple-testing adjustment for eQTL studies that accounts for linkage disequilibrium between variants. Am. J. Hum. Genet. 98, 216–224 (2016).

  30. 30.

    et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).

  31. 31.

    et al. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501, 506–511 (2013).

  32. 32.

    et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).

  33. 33.

    et al. Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types. Nat. Genet. 49, 600–605 (2017).

  34. 34.

    , , & The long-range interaction landscape of gene promoters. Nature 489, 109–113 (2012).

  35. 35.

    et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat. Genet. 47, 598–606 (2015).

  36. 36.

    et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012).

  37. 37.

    et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).

  38. 38.

    et al. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res. 24, 1–13 (2014).

  39. 39.

    et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

  40. 40.

    , , & Global view of enhancer–promoter interactome in human cells. Proc. Natl. Acad. Sci. USA 111, E2191–E2199 (2014).

  41. 41.

    et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).

  42. 42.

    et al. The NHGRI GWAS Catalog, a curated resource of SNP–trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

  43. 43.

    et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415–1429.e19 (2016).

  44. 44.

    et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 33, 272–279 (2017).

  45. 45.

    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).

  46. 46.

    et al. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014).

  47. 47.

    et al. Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression. PLoS Genet. 8, e1002431 (2012).

  48. 48.

    et al. Identification of context-dependent expression quantitative trait loci in whole blood. Nat. Genet. 49, 139–145 (2017).

  49. 49.

    et al. The Netherlands Twin Register biobank: a resource for genetic epidemiological studies. Twin Res. Hum. Genet. 13, 231–245 (2010).

  50. 50.

    et al. DNA methylation changes in the IGF1R gene in birth weight discordant adult monozygotic twins. Twin Res. Hum. Genet. 18, 635–646 (2015).

Download references

Acknowledgements

This research was conducted using the UK Biobank resource under application number 10074. Detailed acknowledgments and funding details are provided for each contributing study in the Supplementary Note.

Author information

Author notes

    • Jorge Esparza-Gordillo

    Present address: GlaxoSmithKline, Stevenage, UK.

    • Manuel A Ferreira
    • , Judith M Vonk
    • , Hansjörg Baurecht
    • , Ingo Marenholz
    • , Chao Tian
    • , Joshua D Hoffman
    • , Quinta Helmer
    • , Annika Tillander
    • , Vilhelmina Ullemar
    • , Jenny van Dongen
    • , Yi Lu
    •  & Franz Rüschendorf

    These authors contributed equally to this work.

    • Norbert Hübner
    • , Stephan Weidinger
    • , Patrik K E Magnusson
    • , Rick Jansen
    • , Eric Jorgenson
    • , Young-Ae Lee
    • , Dorret I Boomsma
    • , Catarina Almqvist
    • , Robert Karlsson
    • , Gerard H Koppelman
    •  & Lavinia Paternoster

    These authors jointly supervised this work.

Affiliations

  1. Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Manuel A Ferreira
    • , Joana A Revez
    • , Jonathan Beesley
    • , Lisa M Bain
    • , Nicholas G Martin
    •  & David L Duffy
  2. Epidemiology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.

    • Judith M Vonk
  3. Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Hansjörg Baurecht
    • , Elke Rodríguez
    • , Melanie Hotze
    •  & Stephan Weidinger
  4. Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.

    • Ingo Marenholz
    • , Franz Rüschendorf
    • , Jorge Esparza-Gordillo
    • , Oliver Hummel
    • , Sarah Grosche
    • , Norbert Hübner
    •  & Young-Ae Lee
  5. Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany.

    • Ingo Marenholz
    • , Jorge Esparza-Gordillo
    • , Sarah Grosche
    •  & Young-Ae Lee
  6. Research, 23andMe, Mountain View, California, USA.

    • Chao Tian
    •  & David A Hinds
  7. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.

    • Joshua D Hoffman
  8. Department of Biological Psychology, Netherlands Twin Register, Vrije University, Amsterdam, the Netherlands.

    • Quinta Helmer
    • , Jenny van Dongen
    • , Jouke-Jan Hottenga
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Annika Tillander
    • , Vilhelmina Ullemar
    • , Yi Lu
    • , Patrik K E Magnusson
    • , Catarina Almqvist
    •  & Robert Karlsson
  10. MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Chris W Medway
    • , Edward Mountjoy
    • , Kimberley Burrows
    • , Ben M Brumpton
    • , Jie Zheng
    •  & Lavinia Paternoster
  11. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

    • Ben M Brumpton
    • , Lars G Fritsche
    • , Maiken E Gabrielsen
    • , Kristian Hveem
    • , Oddgeir L Holmen
    • , Mari Løset
    • , Gonçalo R Abecasis
    •  & Cristen J Willer
  12. Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

    • Ben M Brumpton
  13. Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.

    • John S Witte
  14. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Andre Franke
  15. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • Melanie C Matheson
    •  & Shyamali C Dharmage
  16. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

    • Brunilda Balliu
  17. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Jonas B Nielsen
    •  & Cristen J Willer
  18. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Jonas B Nielsen
    • , Wei Zhou
    •  & Cristen J Willer
  19. HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

    • Kristian Hveem
    •  & Arnulf Langhammer
  20. Department of Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

    • Mari Løset
  21. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Gonçalo R Abecasis
    •  & Cristen J Willer
  22. Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany.

    • Andreas Arnold
  23. Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Georg Homuth
  24. Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany.

    • Carsten O Schmidt
  25. Institute for Respiratory Health, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.

    • Philip J Thompson
  26. Department of Dermatology and Allergology, University Hospital Bonn, Bonn, Germany.

    • Natalija Novak
  27. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Holger Schulz
    •  & Stefan Karrasch
  28. Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany.

    • Holger Schulz
    •  & Stefan Karrasch
  29. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.

    • Stefan Karrasch
  30. Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
  31. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Konstantin Strauch
  32. Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

    • Ronald B Melles
    •  & Eric Jorgenson
  33. Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.

    • Rick Jansen
  34. Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.

    • Catarina Almqvist
  35. University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Pediatric Pulmonology and Pediatric Allergology, and University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.

    • Gerard H Koppelman

Consortia

  1. 23andMe Research Team

    A full list of members and affiliations appears in the Supplementary Note.

  2. AAGC collaborators

    A full list of members and affiliations appears in the Supplementary Note.

  3. BIOS consortium

    A full list of members and affiliations appears in the Supplementary Note.

  4. LifeLines Cohort Study

    A full list of members and affiliations appears in the Supplementary Note.

Authors

  1. Search for Manuel A Ferreira in:

  2. Search for Judith M Vonk in:

  3. Search for Hansjörg Baurecht in:

  4. Search for Ingo Marenholz in:

  5. Search for Chao Tian in:

  6. Search for Joshua D Hoffman in:

  7. Search for Quinta Helmer in:

  8. Search for Annika Tillander in:

  9. Search for Vilhelmina Ullemar in:

  10. Search for Jenny van Dongen in:

  11. Search for Yi Lu in:

  12. Search for Franz Rüschendorf in:

  13. Search for Jorge Esparza-Gordillo in:

  14. Search for Chris W Medway in:

  15. Search for Edward Mountjoy in:

  16. Search for Kimberley Burrows in:

  17. Search for Oliver Hummel in:

  18. Search for Sarah Grosche in:

  19. Search for Ben M Brumpton in:

  20. Search for John S Witte in:

  21. Search for Jouke-Jan Hottenga in:

  22. Search for Gonneke Willemsen in:

  23. Search for Jie Zheng in:

  24. Search for Elke Rodríguez in:

  25. Search for Melanie Hotze in:

  26. Search for Andre Franke in:

  27. Search for Joana A Revez in:

  28. Search for Jonathan Beesley in:

  29. Search for Melanie C Matheson in:

  30. Search for Shyamali C Dharmage in:

  31. Search for Lisa M Bain in:

  32. Search for Lars G Fritsche in:

  33. Search for Maiken E Gabrielsen in:

  34. Search for Brunilda Balliu in:

  35. Search for Jonas B Nielsen in:

  36. Search for Wei Zhou in:

  37. Search for Kristian Hveem in:

  38. Search for Arnulf Langhammer in:

  39. Search for Oddgeir L Holmen in:

  40. Search for Mari Løset in:

  41. Search for Gonçalo R Abecasis in:

  42. Search for Cristen J Willer in:

  43. Search for Andreas Arnold in:

  44. Search for Georg Homuth in:

  45. Search for Carsten O Schmidt in:

  46. Search for Philip J Thompson in:

  47. Search for Nicholas G Martin in:

  48. Search for David L Duffy in:

  49. Search for Natalija Novak in:

  50. Search for Holger Schulz in:

  51. Search for Stefan Karrasch in:

  52. Search for Christian Gieger in:

  53. Search for Konstantin Strauch in:

  54. Search for Ronald B Melles in:

  55. Search for David A Hinds in:

  56. Search for Norbert Hübner in:

  57. Search for Stephan Weidinger in:

  58. Search for Patrik K E Magnusson in:

  59. Search for Rick Jansen in:

  60. Search for Eric Jorgenson in:

  61. Search for Young-Ae Lee in:

  62. Search for Dorret I Boomsma in:

  63. Search for Catarina Almqvist in:

  64. Search for Robert Karlsson in:

  65. Search for Gerard H Koppelman in:

  66. Search for Lavinia Paternoster in:

Contributions

Data collection and analysis in the contributing studies: M.A.F., M.C.M., S.C.D., L.M.B., P.J.T., N.G.M., D.L.D. (AAGC study); J.M.V., G.H.K. (LifeLines study); H.B., E.R., M.H., A.F., N.N., H.S., S.K., C.G., K.S., S.W. (GENEVA study); I.M., F.R., J.E.-G., S.G., A.A., G.H., C.O.S., N.H., Y.-A.L. (GENUFAD studies); C.T., D.A.H. (23andMe study); J.D.H., J.S.W., R.B.M., E.J. (GERA study); Q.H., J.-J.H., G.W., D.I.B. (NTR study); A.T., V.U., Y.L., P.K.E.M., C.A., R.K. (CATSS, TWINGENE and SALTY studies); L.P. (ALSPAC study); B.M.B., L.G.F., M.E.G., J.B.N., W.Z., K.H., A.L., O.L.H., M.L., G.R.A., C.J.W. (HUNT study); L.P., M.A.F. (UK Biobank study). Methylation analysis: J.v.D., D.I.B., R.J. Biological and drug annotation: M.A.F., C.W.M., E.M., K.B., O.H., J.Z., J.A.R., J.B., B.B. Quality control, meta-analysis, tables and figures: M.A.F. Writing group: M.A.F., J.M.V., I.M., C.T., J.D.H., Q.H., A.T., V.U., J.v.D., Y.L., J.E.-G., B.M.B., J.B., S.C.D., S.W., P.K.E.M., R.J., E.J., Y.-A.L., D.I.B., C.A., R.K., G.H.K., L.P. Study design and management: M.A.F., D.A.H., B.M.B., S.W., P.K.E.M., R.J., E.J., Y.-A.L., D.I.B., C.A., R.K., G.H.K., L.P.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Manuel A Ferreira.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Note

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Tables

    Supplementary Tables 1–29