Letter | Published:

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Nature Genetics volume 47, pages 14491456 (2015) | Download Citation

Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Gene Expression Omnibus

References

  1. 1.

    & Atopic dermatitis. Lancet 10.1016/S0140-6736(15)00149-X (13 September 2015).

  2. 2.

    , & The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data. J. Eur. Acad. Dermatol. Venereol. 26, 1067–1073 (2012).

  3. 3.

    , & Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365, 1315–1327 (2011).

  4. 4.

    et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 38, 441–446 (2006).

  5. 5.

    et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J. Allergy Clin. Immunol. 123, 1361–1370 (2009).

  6. 6.

    et al. A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. Hum. Mol. Genet. 22, 4841–4856 (2013).

  7. 7.

    et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat. Genet. 45, 808–812 (2013).

  8. 8.

    et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat. Genet. 44, 1222–1226 (2012).

  9. 9.

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

  10. 10.

    et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat. Genet. 43, 690–694 (2011).

  11. 11.

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

  12. 12.

    et al. A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. J. Allergy Clin. Immunol. 132, 371–377 (2013).

  13. 13.

    , , , & Evaluating empirical bounds on complex disease genetic architecture. Nat. Genet. 45, 1418–1427 (2013).

  14. 14.

    et al. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat. Genet. 45, 907–911 (2013).

  15. 15.

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

  16. 16.

    et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am. J. Hum. Genet. 84, 581–593 (2009).

  17. 17.

    et al. Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations. PLoS Genet. 7, e1002170 (2011).

  18. 18.

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

  19. 19.

    et al. Variants of DENND1B associated with asthma in children. N. Engl. J. Med. 362, 36–44 (2010).

  20. 20.

    et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat. Genet. 43, 893–896 (2011).

  21. 21.

    et al. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nat. Genet. 45, 902–906 (2013).

  22. 22.

    et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

  23. 23.

    et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 44, 1341–1348 (2012).

  24. 24.

    International Genetics of Ankylosing Spondylitis Consortium. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730–738 (2013).

  25. 25.

    International Multiple Sclerosis Genetics Consortium. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

  26. 26.

    et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

  27. 27.

    et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet. 7, e1002293 (2011).

  28. 28.

    , & An association between ulcerative colitis and atopic dermatitis, diseases of impaired superficial barriers. J. Invest. Dermatol. 123, 999–1000 (2004).

  29. 29.

    , , & Environmental factors and risk of developing paediatric inflammatory bowel disease—a population based study 2007–2009. J. Crohns Colitis 7, 79–88 (2013).

  30. 30.

    et al. Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study. Gut 54, 357–363 (2005).

  31. 31.

    & Disease concomitance in psoriasis. J. Am. Acad. Dermatol. 32, 982–986 (1995).

  32. 32.

    et al. Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am. J. Hum. Genet. 96, 104–120 (2015).

  33. 33.

    et al. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 6, e1001058 (2010).

  34. 34.

    Wellcome Trust Case Control Consortium. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).

  35. 35.

    et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat. Genet. 44, 1084–1089 (2012).

  36. 36.

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  37. 37.

    et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat. Biotechnol. 28, 1045–1048 (2010).

  38. 38.

    , & The origins and functions of dendritic cells and macrophages in the skin. Nat. Rev. Immunol. 14, 417–428 (2014).

  39. 39.

    & Langerhans cells in innate defense against pathogens. Trends Immunol. 31, 452–459 (2010).

  40. 40.

    The role of microorganisms in atopic dermatitis. Clin. Exp. Immunol. 144, 1–9 (2006).

  41. 41.

    , & Does “autoreactivity” play a role in atopic dermatitis? J. Allergy Clin. Immunol. 129, 1209–1215 (2012).

  42. 42.

    et al. Transgenic overexpression of G5PR that is normally augmented in centrocytes impairs the enrichment of high-affinity antigen-specific B cells, increases peritoneal B-1a cells, and induces autoimmunity in aged female mice. J. Immunol. 189, 1193–1201 (2012).

  43. 43.

    , & IL-7 in human health and disease. Semin. Immunol. 24, 218–224 (2012).

  44. 44.

    et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. 39, 1083–1091 (2007).

  45. 45.

    et al. Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis. Nat. Genet. 39, 1108–1113 (2007).

  46. 46.

    et al. Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proc. Natl. Acad. Sci. USA 110, E1761–E1770 (2013).

  47. 47.

    , , & Immunologic abnormalities exhibited in IL-7 transgenic mice with dermatitis. J. Invest. Dermatol. 110, 740–745 (1998).

  48. 48.

    et al. A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123, 2978–2987 (2014).

  49. 49.

    et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).

  50. 50.

    , , & Clan genomics and the complex architecture of human disease. Cell 147, 32–43 (2011).

  51. 51.

    et al. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. Cell 155, 70–80 (2013).

  52. 52.

    , , & The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res. 67, 11001–11011 (2007).

  53. 53.

    et al. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J. Allergy Clin. Immunol. 133, 1564–1571 (2014).

  54. 54.

    , & Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30, 95–114 (2012).

  55. 55.

    , , , & Ets-1 is a negative regulator of Th17 differentiation. J. Exp. Med. 204, 2825–2835 (2007).

  56. 56.

    et al. Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators. J. Cell Sci. 123, 3566–3575 (2010).

  57. 57.

    et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N. Engl. J. Med. 371, 130–139 (2014).

  58. 58.

    et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J. Allergy Clin. Immunol. 129, 840–845 (2012).

  59. 59.

    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).

  60. 60.

    Transethnic meta-analysis of genomewide association studies. Genet. Epidemiol. 35, 809–822 (2011).

  61. 61.

    et al. Comparing methods for performing trans-ethnic meta-analysis of genome-wide association studies. Hum. Mol. Genet. 22, 2303–2311 (2013).

  62. 62.

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

  63. 63.

    A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet. 74, 765–769 (2004).

  64. 64.

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

  65. 65.

    et al. Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis. J. Allergy Clin. Immunol. 134, 82–91 (2014).

  66. 66.

    et al. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J. Allergy Clin. Immunol. 128, 583–593 (2011).

  67. 67.

    et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).

  68. 68.

    et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

  69. 69.

    , & Uncovering the total heritability explained by all true susceptibility variants in a genome-wide association study. Genet. Epidemiol. 35, 447–456 (2011).

Download references

Acknowledgements

This publication is the work of the authors, and L.P. will serve as guarantor for the contents of this paper. This research was specifically funded by an MRC Population Health Scientist Fellowship awarded to L.P. (MR/J012165/1). D.M.E. is supported by an Australian Research Council Future Fellowship (FT130101709) and a Medical Research Council program grant (MC_UU_12013/4). Individual study acknowledgment and funding statements can be found in the Supplementary Note.

Author information

Author notes

    • Lavinia Paternoster
    •  & Marie Standl

    These authors contributed equally to this work.

    • David M Evans
    •  & Stephan Weidinger

    These authors jointly supervised this work.

Affiliations

  1. Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • Lavinia Paternoster
    • , John P Kemp
    • , Jie Zheng
    • , George Davey Smith
    • , Caroline L Relton
    •  & David M Evans
  2. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Lavinia Paternoster
    • , Wendy L McArdle
    • , A John Henderson
    • , John P Kemp
    • , Jie Zheng
    • , George Davey Smith
    •  & David M Evans
  3. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Marie Standl
    • , Carla M T Tiesler
    • , Elisabeth Thiering
    •  & Joachim Heinrich
  4. Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Johannes Waage
    • , Klaus Bønnelykke
    • , Eskil Kreiner-Møller
    •  & Hans Bisgaard
  5. Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Hansjörg Baurecht
    • , Melanie Hotze
    • , Elke Rodríguez
    • , Regina Fölster-Holst
    •  & Stephan Weidinger
  6. Population Health Research Institute, St. George's, University of London, London, UK.

    • David P Strachan
  7. Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester and University Hospital of South Manchester National Health Service (NHS) Foundation Trust, Manchester, UK.

    • John A Curtin
    • , Adnan Custovic
    •  & Angela Simpson
  8. 23andMe, Inc., Mountain View, California, USA.

    • Chao Tian
    • , Joyce Y Tung
    •  & David A Hinds
  9. Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.

    • Atsushi Takahashi
  10. Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.

    • Jorge Esparza-Gordillo
    • , Ingo Marenholz
    • , Birgit Kalb
    • , Anja Matanovic
    • , Franz Rüschendorf
    • , Anja Bauerfeind
    • , Norbert Hübner
    •  & Young-Ae Lee
  11. Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité–Universitätsmedizin Berlin, Berlin, Germany.

    • Jorge Esparza-Gordillo
    • , Ingo Marenholz
    • , Anja Matanovic
    •  & Young-Ae Lee
  12. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Alexessander Couto Alves
  13. National Allergy Research Centre, Department of Dermatology and Allergology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Jacob P Thyssen
  14. Department of Pediatrics, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Herman T den Dekker
    • , Johan C de Jongste
    • , Vincent W V Jaddoe
    •  & Liesbeth Duijts
  15. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Herman T den Dekker
    • , Fernando Rivadeneira
    • , Albert Hofman
    • , Vincent W V Jaddoe
    • , André G Uitterlinden
    •  & Liesbeth Duijts
  16. Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Herman T den Dekker
    • , Fernando Rivadeneira
    • , Vincent W V Jaddoe
    • , Niels J Elbert
    •  & Liesbeth Duijts
  17. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Manuel A Ferreira
    •  & Nicholas G Martin
  18. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Elisabeth Altmaier
    •  & Christian Gieger
  19. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Elisabeth Altmaier
    • , Annette Peters
    •  & Christian Gieger
  20. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Elisabeth Altmaier
    • , Janina S Ried
    •  & Christian Gieger
  21. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Patrick M A Sleiman
    • , Jin Li
    •  & Hakon Hakonarson
  22. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Patrick M A Sleiman
    •  & Hakon Hakonarson
  23. Institute of Dermatology, Anhui Medical University, Hefei, China.

    • Feng Li Xiao
    • , Xian Bo Zuo
    • , Xiao Dong Zheng
    • , Xian Yong Yin
    • , Liang Dan Sun
    •  & Xue Jun Zhang
  24. Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

    • Juan R Gonzalez
    • , Mariona Bustamante
    • , Natàlia Vilor-Tejedor
    •  & Jordi Sunyer
  25. Pompeu Fabra University (UPF), Barcelona, Spain.

    • Juan R Gonzalez
    • , Mariona Bustamante
    • , Natàlia Vilor-Tejedor
    •  & Jordi Sunyer
  26. Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.

    • Juan R Gonzalez
    • , Mariona Bustamante
    • , Natàlia Vilor-Tejedor
    •  & Jordi Sunyer
  27. Pediatric Pneumology and Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany.

    • Birgit Kalb
    •  & Susanne Lau
  28. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Maria Pino-Yanes
    • , Donglei Hu
    • , Celeste Eng
    • , Scott Huntsman
    •  & Esteban G Burchard
  29. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.

    • Maria Pino-Yanes
  30. Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.

    • Maria Pino-Yanes
  31. University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen Research Institute for Asthma and COPD (GRIAC), the Netherlands.

    • Cheng-Jian Xu
    •  & Dirkje S Postma
  32. University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen Research Institute for Asthma and COPD (GRIAC), the Netherlands.

    • Cheng-Jian Xu
  33. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Lisbeth Carstensen
    • , Bjarke Feenstra
    • , Frank Geller
    •  & Mads Melbye
  34. Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, the Netherlands.

    • Maria M Groen-Blokhuis
    • , Jouke Jan Hottenga
    • , Christel M Middeldorp
    •  & Dorret I Boomsma
  35. King's College London Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Cristina Venturini
    • , Pirro Hysi
    • , Veronique Bataille
    • , Tim Spector
    •  & Daniel Glass
  36. School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.

    • Craig E Pennell
    •  & Carol A Wang
  37. Medical Research Council (MRC) Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

    • Sheila J Barton
    •  & Keith M Godfrey
  38. Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA.

    • Albert M Levin
  39. Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.

    • Ivan Curjuric
    • , Ashish Kumar
    • , Medea Imboden
    •  & Nicole M Probst-Hensch
  40. University of Basel, Basel, Switzerland.

    • Ivan Curjuric
    • , Ashish Kumar
    • , Medea Imboden
    •  & Nicole M Probst-Hensch
  41. Centre for Genomic Regulation (CRG), Barcelona, Spain.

    • Mariona Bustamante
  42. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Gabrielle A Lockett
    •  & John W Holloway
  43. Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.

    • Jonas Bacelis
    •  & Bo Jacobsson
  44. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Supinda Bunyavanich
  45. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.

    • Rachel A Myers
    •  & Carole Ober
  46. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Ashish Kumar
    •  & Erik Melén
  47. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Ashish Kumar
    •  & Momoko Horikoshi
  48. Laboratory for Respiratory and Allergic Diseases, Center for Integrative Medical Sciences, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.

    • Tomomitsu Hirota
    •  & Mayumi Tamari
  49. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.

    • Michiaki Kubo
  50. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.

    • John P Kemp
    •  & David M Evans
  51. Klinik für Kinder- und Jugendmedizin, Technical University Dresden, Dresden, Germany.

    • Min Ae Lee-Kirsch
  52. Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany.

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

    • Georg Homuth
  54. Institute for Community Medicine, Study of Health in Pomerania/KEF (Klinisch-Epidemiologische Forschung), University Medicine Greifswald, Greifswald, Germany.

    • Carsten O Schmidt
  55. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Elisabeth Mangold
    • , Sven Cichon
    •  & Markus M Nöthen
  56. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Sven Cichon
    •  & Markus M Nöthen
  57. Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.

    • Sven Cichon
  58. Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Sven Cichon
  59. Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Jülich, Jülich, Germany.

    • Sven Cichon
  60. Institute of Social Medicine, Epidemiology and Health Economics, Charité–Universitätsmedizin Berlin, Berlin, Germany.

    • Thomas Keil
  61. Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.

    • Thomas Keil
  62. DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.

    • Annette Peters
  63. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Andre Franke
  64. Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.

    • Wolfgang Lieb
  65. Department of Dermatology and Allergy, University of Bonn Medical Center, Bonn, Germany.

    • Natalija Novak
  66. Unit of Living Environment and Health, National Institute for Health and Welfare, Kuopio, Finland.

    • Juha Pekkanen
  67. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Juha Pekkanen
  68. Center for Life-Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.

    • Sylvain Sebert
    •  & Marjo-Riitta Jarvelin
  69. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Sylvain Sebert
    •  & Marjo-Riitta Jarvelin
  70. Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.

    • Lise L Husemoen
    •  & Allan Linneberg
  71. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Niels Grarup
  72. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Fernando Rivadeneira
    •  & André G Uitterlinden
  73. Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Suzanne G M A Pasmans
    •  & Niels J Elbert
  74. Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.

    • Guy B Marks
  75. Lung Institute of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.

    • Philip J Thompson
  76. School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

    • Philip J Thompson
  77. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • Melanie C Matheson
  78. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.

    • Colin F Robertson
  79. National Children's Research Centre, Crumlin, Dublin, Ireland.

    • Maeve A McAleer
    •  & Alan D Irvine
  80. Department of Pediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.

    • Maeve A McAleer
    • , Grainne M O'Regan
    •  & Alan D Irvine
  81. Clinical Medicine, Trinity College Dublin, Dublin, Ireland.

    • Caoimhe M R Fahy
    •  & Alan D Irvine
  82. Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, UK.

    • Linda E Campbell
    • , W H Irwin McLean
    •  & Sara J Brown
  83. Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine of Charles University, Prague, Czech Republic.

    • Milan Macek
  84. Department of Clinical Allergology, Pomeranian Medical University, Szczecin, Poland.

    • Michael Kurek
  85. Division of Metabolic Diseases and Nutritional Medicine, Ludwig Maximilians University of Munich, Dr. von Hauner Children's Hospital, Munich, Germany.

    • Carla M T Tiesler
    •  & Elisabeth Thiering
  86. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan, USA.

    • Badri Pahukasahasram
    •  & L Keoki Williams
  87. School of Nursing, University of Michigan, Ann Arbor, Michigan, USA.

    • James J Yang
  88. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

    • Caroline L Relton
  89. Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.

    • Ronny Myhre
    • , Wenche Nystad
    •  & Bo Jacobsson
  90. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Scott T Weiss
    •  & Benjamin A Raby
  91. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Deborah A Meyers
  92. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Cilla Söderhäll
  93. Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden.

    • Cilla Söderhäll
  94. Sachs' Children's Hospital, Stockholm, Sweden.

    • Erik Melén
  95. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

    • John W Holloway
  96. Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.

    • Jordi Sunyer
  97. Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.

    • L Keoki Williams
  98. National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK.

    • Keith M Godfrey
  99. Institute for Health and Care Research (EMGO), VU University, Amsterdam, the Netherlands.

    • Dorret I Boomsma
  100. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Mads Melbye
    •  & Allan Linneberg
  101. Department of Medicine, Stanford School of Medicine, Stanford, California, USA.

    • Mads Melbye
  102. University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.

    • Gerard H Koppelman
  103. Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UK.

    • Deborah Jarvis
  104. Department of Epidemiology and Biostatistics, Medical Research Council–Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Deborah Jarvis
  105. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.

    • Esteban G Burchard
  106. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.

    • Allan Linneberg
  107. Department of Epidemiology and Biostatistics, Medical Research Council–Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Marjo-Riitta Jarvelin
  108. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  109. Department of Dermatology, Ninewells Hospital and Medical School, Dundee, UK.

    • Sara J Brown

Consortia

  1. the EArly Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium

    Australian Asthma Genetics Consortium(AAGC)

Authors

    Contributions

    Conceived and designed the experiments: L.P., M.S., H. Baurecht, D.P.S., J.A.C., K.B., J.P.T., H.T.d.D., P.M.A.S., F.L.X., M.B., J.Y.T., A.J.H., G.D.S., E.R., J.P., L.L.H., J.C.d.J., F. Rivadeneira, A.H., V.W.V.J., S.G.M.A.P., N.J.E., A.G.U., D.S.P., B.F., A.C., D.A.M., E. Melén, C.O., A.S., B.J., J.W.H., H. Bisgaard, J.S., N.M.P.-H., L.K.W., K.M.G., D.I.B., M. Melbye, G.H.K., Y.-A.L., N.H., D.J., X.J.Z., H.H., L.D., A.L., M.-R.J., M.T., S.J. Brown, J.H., D.M.E., S.W.

    Performed the experiments: L.P., K.B., P.M.A.S., F.L.X., M.B., E.K.-M., G.A.L., M. Kubo, W.L.M., J.P.K., J.Z., E.R., F. Rivadeneira, A.G.U., J.L., X.Y.Y., L.D.S., L.E.C., A.M., C.E., D.S.P., C.M.T.T., M.I., S.H., N.V.-T., B.J., H. Bisgaard, N.M.P.-H., L.K.W., K.M.G., G.H.K., A.L., S.J. Brown, D.M.E., S.W.

    Performed the statistical analysis: L.P., M.S., J.W., H. Baurecht, M. Hotze, D.P.S., J.A.C., C.T., A.T., A.B., A.C.A., H.T.d.D., M.A.F., E.A., P.M.A.S., J.R.G., I.M., J.E.-G., M.P.-Y., C.-J.X., L.C., M.M.G.-B., C.V., S.J. Barton, A.M.L., I.C., E.K.-M., G.A.L., S.B., R.A.M., F. Rüschendorf, A.K., J.P.K., J.Z., L.L.H., F. Rivadeneira, N.J.E., J.S.R., J.L., X.B.Z., X.D.Z., D.H., B.F., F.G., P.H., C.M.T.T., E.T., B.P., J.J.Y., N.V.-T., R.M., C.A.W., L.D., D.A.H., D.M.E.

    Analyzed the data: L.P., M.S., J.W., H. Baurecht, M. Hotze, D.P.S., J.A.C., K.B., C.T., A.B., A.C.A., J.P.T., H.T.d.D., M.A.F., E.A., P.M.A.S., F.L.X., J.R.G., I.M., J.E.-G., M.P.-Y., C.-J.X., L.C., M.M.G.-B., C.V., S.J. Barton, A.M.L., I.C., G.A.L., J.B., S.B., R.A.M., F. Rüschendorf, A.K., A.J.H., M. Horikoshi, S.S., L.L.H., F. Rivadeneira, N.J.E., A.G.U., M.C.M., J.S.R., J.L., X.B.Z., X.D.Z., X.Y.Y., D.H., B.F., F.G., J.J.H., C.M.M., P.H., C.M.T.T., E.T., B.P., J.J.Y., M.I., S.H., N.V.-T., E. Melén, B.J., L.K.W., C.A.W., Y.-A.L., N.H., L.D., A.L., M.T., D.A.H., D.G., S.J. Brown, D.M.E.

    Contributed reagents, material and/or analysis tools: L.P., J.W., H. Baurecht, M. Hotze, C.T., H.T.d.D., P.M.A.S., M.P.-Y., C.E.P., A.M.L., M.B., S.B., T.H., M. Kubo, W.L.M., J.Z., G.D.S., M. Macek, M. Kurek, M.A.L.-K., E. Mangold, A.P., A.F., W.L., N.N., R.F.-H., N.G., J.C.d.J., F. Rivadeneira, A.H., V.W.V.J., S.G.M.A.P., N.J.E., A.G.U., G.B.M., P.J.T., C.F.R., J.L., L.D.S., M.A.M., G.M.O'R., C.M.R.F., A.A., G.H., C.O.S., B.K., D.H., C.E., D.S.P., V.B., T.S., B.P., J.J.Y., C.L.R., S.T.W., D.A.M., S.C., T.K., C.S., E. Melén, S.L., C.O., B.A.R., B.J., J.W.H., J.S., L.K.W., K.M.G., M. Melbye, G.H.K., Y.-A.L., N.H., D.J., W.H.I.M., A.D.I., X.J.Z., H.H., C.G., E.G.B., N.G.M., L.D., M.-R.J., M.M.N., M.T., D.A.H., S.J. Brown, J.H., S.W.

    Wrote the manuscript: L.P., M.S., J.W., H. Baurecht, M. Hotze, D.P.S., J.A.C., K.B., A.J.H., S.J. Brown, D.M.E., S.W.

    Revised and reviewed the paper: L.P., M.S., J.W., H. Baurecht, M. Hotze, D.P.S., J.A.C., K.B., C.T., A.T., A.B., A.C.A., J.P.T., H.T.d.D., M.A.F., E.A., P.M.A.S., F.L.X., J.R.G., I.M., J.E.-G., M.P.-Y., C.-J.X., L.C., M.M.G.-B., C.V., C.E.P., S.J. Barton, A.M.L., I.C., M.B., E.K.-M., G.A.L., S.B., R.A.M., F. Rüschendorf, A.K., J.Y.T., T.H., M. Kubo, W.L.M., A.J.H., J.P.K., J.Z., G.D.S., M. Macek, M. Kurek, M.A.L.-K., E. Mangold, E.R., A.P., A.F., W.L., N.N., R.F.-H., M. Horikoshi, J.P., S.S., L.L.H., N.G., J.C.d.J., F. Rivadeneira, A.H., V.W.V.J., S.G.M.A.P., N.J.E., A.G.U., G.B.M., P.J.T., M.C.M., C.F.R., J.S.R., J.L., X.B.Z., X.D.Z., X.Y.Y., L.D.S., M.A.M., G.M.O'R., C.M.R.F., L.E.C., A.A., G.H., A.M., C.O.S., B.K., D.H., C.E., D.S.P., B.F., F.G., J.J.H., C.M.M., P.H., V.B., T.S., C.M.T.T., E.T., B.P., J.J.Y., M.I., S.H., N.V.-T., C.L.R., R.M., W.N., A.C., S.T.W., D.A.M., S.C., T.K., C.S., E. Melén, S.L., C.O., B.A.R., A.S., B.J., J.W.H., H. Bisgaard, J.S., N.M.P.-H., L.K.W., K.M.G., C.A.W., D.I.B., M. Melbye, G.H.K., Y.-A.L., N.H., D.J., W.H.I.M., A.D.I., X.J.Z., H.H., C.G., E.G.B., N.G.M., L.D., A.L., M.-R.J., M.M.N., M.T., D.A.H., D.G., S.J. Brown, J.H., D.M.E., S.W.

    AAGC provided results for the discovery analysis.

    Competing interests

    C.T., D.A.H. and J.Y.T. are employees of and own stock or stock options in 23andMe, Inc. K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional and pharmaceutical products. He is part of an academic consortium that has received funding from Abbott Nutrition, Nestec and Danone. The University of Groningen has received money for D.S.P. in the context of an unrestricted educational grant for research from AstraZeneca. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda and TEVA. A.C. reports personal fees from AstraZeneca, personal fees from Novartis and personal fees from ThermoFisher given outside the context of the current manuscript. A.S. reports personal fees from GlaxoSmithKline and personal fees from ThermoFisher given outside the context of the current manuscript.

    Corresponding author

    Correspondence to Lavinia Paternoster.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Figures 1–8, Supplementary Tables 1–4, 11–16, 22 and 23, and Supplementary Note.

    Excel files

    1. 1.

      Supplementary Tables 5–10

      Look-ups of known SNPs for various autoimmune diseases.

    2. 2.

      Supplementary Tables 17–21

      Functional investigations of credible SNPs.

    About this article

    Publication history

    Received

    Accepted

    Published

    DOI

    https://doi.org/10.1038/ng.3424

    Further reading

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