Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population

Nature Genetics volume 44, pages1222–1226(2012)Cite this article

Subjects

Abstract

Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (Pcombined = 8.36 × 10−18), the major histocompatibility complex (MHC) region (P = 8.38 × 10−20), OR10A3-NLRP10 (P = 1.54 × 10−22), GLB1 (P = 2.77 × 10−16), CCDC80 (P = 1.56 × 10−19), CARD11 (P = 7.83 × 10−9), ZNF365 (P = 5.85 × 10−20) and CYP24A1-PFDN4 (P = 1.65 × 10−8). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Figure 1: Manhattan plot showing the −log10P values of 606,164 SNPs in the GWAS for 1,472 Japanese atopic dermatitis cases and 7,971 controls plotted against their respective positions on autosomes and the X chromosome.
Figure 2: Regional plots of association results within eight newly identified susceptibility regions for atopic dermatitis.

References

  1. 1

    Bieber, T. Mechanisms of disease: atopic dermatitis. N. Engl. J. Med. 358, 1483–1494 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Boguniewicz, M. & Leung, D.Y. Recent insights into atopic dermatitis and implications for management of infectious complications. J. Allergy Clin. Immunol. 125, 4–13 (2010).

    Article  Google Scholar 

  3. 3

    Palmer, C.N. 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).

    CAS  Article  Google Scholar 

  4. 4

    Irvine, A.D., McLean, W.H. & Leung, D.Y. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365, 1315–1327 (2011).

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

    Sun, L.D. 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).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    Johnston, A. et al. IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. J. Immunol. 186, 2613–2622 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Liew, F.Y., Pitman, N.I. & McInnes, I.B. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat. Rev. Immunol. 10, 103–110 (2010).

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Torgerson, D.G. et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat. Genet. 43, 887–892 (2011).

    CAS  Article  Google Scholar 

  12. 12

    Horton, R. et al. Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889–899 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Altrichter, S. et al. Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J. Invest. Dermatol. 128, 2232–2239 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Magalhaes, J.G. et al. What is new with Nods? Curr. Opin. Immunol. 23, 29–34 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Imamura, R. et al. Anti-inflammatory activity of PYNOD and its mechanism in humans and mice. J. Immunol. 184, 5874–5884 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Vestergaard, C. et al. A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin. J. Invest. Dermatol. 115, 640–646 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Tremblay, F. et al. Bidirectional modulation of adipogenesis by the secreted protein Ccdc80/DRO1/URB. J. Biol. Chem. 284, 8136–8147 (2009).

    CAS  Article  Google Scholar 

  18. 18

    Lopez, R.G. et al. C/EBPα and β couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation. Nat. Cell Biol. 11, 1181–1190 (2009).

    CAS  Article  Google Scholar 

  19. 19

    Jung, K. et al. Peroxisome proliferator-activated receptor γ–mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice. J. Allergy Clin. Immunol. 127, 420–429 (2011).

    CAS  Article  Google Scholar 

  20. 20

    Hara, H. et al. Cell type–specific regulation of ITAM-mediated NF-κB activation by the adaptors, CARMA1 and CARD9. J. Immunol. 181, 918–930 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Blonska, M. et al. CARMA1 controls Th2 cell–specific cytokine expression through regulating JunB and GATA3 transcription factors. J. Immunol. 188, 3160–3168 (2012).

    CAS  Article  Google Scholar 

  22. 22

    Jun, J.E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Safford, M. et al. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat. Immunol. 6, 472–480 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Hart, P.H., Gorman, S. & Finlay-Jones, J.J. Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat. Rev. Immunol. 11, 584–596 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Peroni, D.G. et al. Correlation between serum 25–hydroxyvitamin D levels and severity of atopic dermatitis in children. Br. J. Dermatol. 164, 1078–1082 (2011).

    CAS  Article  Google Scholar 

  26. 26

    Wang, R. et al. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 106, 13439–13444 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Spergel, J.M. & Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 112, S118–S127 (2003).

    Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    Hanifin, J.M. & Rajka, R.G. Diagnostic features of atopic dermatitis. Acta Derm. (Stockholm) 92 (suppl. 92), 44–47 (1980).

    Google Scholar 

  32. 32

    Nakamura, Y. The BioBank Japan Project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).

    PubMed  Google Scholar 

  33. 33

    Takata, R. et al. Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat. Genet. 42, 751–754 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Breslow, N.E. & Day, N.E. Statistical methods in cancer research. Volume II—the design and analysis of cohort studies. IARC Sci. Publ. 1–406 (1987).

  36. 36

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

    CAS  Article  Google Scholar 

  37. 37

    Li, Y. et al. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

    Article  Google Scholar 

  38. 38

    Li, Y. et al. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    CAS  Article  Google Scholar 

  39. 39

    1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

Download references

Acknowledgements

We thank all the individuals who participated in the study and also thank the collaborating physicians for helping with sample collection. We are grateful to the members of BioBank Japan and the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. We thank M.T. Shimizu, H. Sekiguchi, A.I. Jodo, N. Kawaraichi and the technical staff of the Center for Genomic Medicine for providing technical assistance and K. Barrymore for proofreading this manuscript. This work was conducted as part of the BioBank Japan Project, which is supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was also partly supported by grants from the Ministry of Health, Labour and Welfare, Japan.

Author information

Affiliations

  1. Laboratory for Respiratory Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Tomomitsu Hirota, Shota Tanaka & Mayumi Tamari

  2. Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Minato-ku, Japan

    Atsushi Takahashi

  3. Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Michiaki Kubo

  4. Laboratory for Medical Informatics, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Tatsuhiko Tsunoda

  5. Department of Otorhinolaryngology, Fukui Medical University, Matsuoka, Japan

    Kaori Tomita, Masafumi Sakashita, Takechiyo Yamada & Shigeharu Fujieda

  6. Department of Otolaryngology–Head and Neck Surgery, University of Yamanashi, Faculty of Medicine, Chuo, Japan

    Shota Tanaka

  7. Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan

    Satoru Doi

  8. Miyatake Asthma Clinic, Osaka, Japan

    Akihiko Miyatake

  9. Nonprofit Organization (NPO) Japan Health Promotion Supporting Network, Wakayama, Japan

    Tadao Enomoto

  10. Atopy Research Center, Juntendo University School of Medicine, Bunkyo-ku, Japan

    Chiharu Nishiyama, Nobuhiro Nakano, Keiko Maeda, Ko Okumura & Hideoki Ogawa

  11. Department of Dermatology, Juntendo University School of Medicine, Bunkyo-ku, Japan

    Shigaku Ikeda

  12. Department of Medical Genetics, Majors of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    Emiko Noguchi

  13. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Saitama, Japan

    Emiko Noguchi

  14. Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

    Tohru Sakamoto & Nobuyuki Hizawa

  15. Department of Dermatology, Takao Hospital, Kyoto, Japan

    Koji Ebe

  16. Department of Dermatology, Jikei University School of Medicine, Minato-ku, Japan

    Hidehisa Saeki

  17. Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Japan

    Takashi Sasaki, Tamotsu Ebihara & Masayuki Amagai

  18. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Satoshi Takeuchi & Masutaka Furue

  19. Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Japan

    Yusuke Nakamura

Authors
  1. Tomomitsu Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsushi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michiaki Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatsuhiko Tsunoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaori Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masafumi Sakashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takechiyo Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shigeharu Fujieda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shota Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satoru Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Akihiko Miyatake
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tadao Enomoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chiharu Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nobuhiro Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Keiko Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ko Okumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hideoki Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Shigaku Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Emiko Noguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Tohru Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Nobuyuki Hizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Koji Ebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Hidehisa Saeki
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Takashi Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Tamotsu Ebihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Masayuki Amagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Satoshi Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Masutaka Furue
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Mayumi Tamari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.H. and M.T. designed the study and drafted the manuscript. A.T. and T.T. analyzed the GWAS data. T.H., K.T., S. Tanaka and M.K. performed the genotyping for the GWAS. M.S., T.Y., S.F., S.D., A.M., T. Enomoto, C.N., N.N., K.M., S.I., K.O., H.O., E.N., T. Sakamoto, N.H., K.E., H.S., T. Sasaki, T. Ebihara, M.A., S. Takeuchi and M.F. recruited subjects and participated in the diagnostic evaluations. M.T. wrote the manuscript. M.K. and Y.N. contributed to the overall GWAS study design.

Corresponding author

Correspondence to Mayumi Tamari.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–6 (PDF 3895 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hirota, T., Takahashi, A., Kubo, M. et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 44, 1222–1226 (2012). https://doi.org/10.1038/ng.2438

Download citation

Further reading

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