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.

  • Letter
  • Published:

Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese

Abstract

To fine map association signals of human leukocyte antigen (HLA) variants in the major histocompatibility complex (MHC) region, we constructed a Japanese population-specific reference panel (n = 908). We conducted trans-ancestry comparisons of linkage disequilibrium (LD) and haplotype structure for HLA variants using an entropy-based LD measurement, ɛ, and a visualization tool to capture high-dimensional variables. Our Japanese reference panel exhibited stronger LD between HLA genes than European or other East Asian populations, characterized by one population-specific common long-range HLA haplotype. We applied HLA imputation to genome-wide association study (GWAS) data for Graves' disease in Japanese (n = 9,003) and found that amino acid polymorphisms of multiple class I and class II HLA genes independently contribute to disease risk (HLA-DPB1, HLA-A, HLA-B and HLA-DRB1; P < 2.3 × 10−6), with the strongest impact at HLA-DPB1 (P = 1.6 × 10−42). Our study illustrates the value of population-specific HLA reference panels.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Trans-ancestry comparisons of LD and haplotype structure for HLA genes.
Figure 2: Regional association plots of HLA variants in the MHC region and Graves' disease risk in Japanese.
Figure 3: Graves' disease risk-associated HLA amino acid positions identified by stepwise conditional association analysis.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. de Bakker, P.I. & Raychaudhuri, S. Interrogating the major histocompatibility complex with high-throughput genomics. Hum. Mol. Genet. 21, R29–R36 (2012).

    Article  CAS  Google Scholar 

  2. International HIV Controllers Study. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010).

  3. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    Article  CAS  Google Scholar 

  4. Okada, Y. et al. Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1. Arthritis Rheum. 60, 3582–3590 (2009).

    Article  CAS  Google Scholar 

  5. Okada, Y. et al. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. Am. J. Hum. Genet. 95, 162–172 (2014).

    Article  CAS  Google Scholar 

  6. Kamatani, Y. et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat. Genet. 41, 591–595 (2009).

    Article  CAS  Google Scholar 

  7. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  8. Okada, Y. et al. HLA-DRB1*0901 lowers anti-cyclic citrullinated peptide antibody levels in Japanese patients with rheumatoid arthritis. Ann. Rheum. Dis. 69, 1569–1570 (2010).

    Article  CAS  Google Scholar 

  9. Jia, X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE 8, e64683 (2013).

    Article  CAS  Google Scholar 

  10. Han, B. et al. Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity. Am. J. Hum. Genet. 94, 522–532 (2014).

    Article  CAS  Google Scholar 

  11. Okada, Y. et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum. Mol. Genet. 23, 6916–6926 (2014).

    Article  CAS  Google Scholar 

  12. Pillai, N.E. et al. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations. Hum. Mol. Genet. 23, 4443–4451 (2014).

    Article  CAS  Google Scholar 

  13. Kawashima, M., Ohashi, J., Nishida, N. & Tokunaga, K. Evolutionary analysis of classical HLA class I and II genes suggests that recent positive selection acted on DPB1*04:01 in Japanese population. PLoS ONE 7, e46806 (2012).

    Article  CAS  Google Scholar 

  14. de Bakker, P.I. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

    Article  CAS  Google Scholar 

  15. Gourraud, P.A. et al. HLA diversity in the 1000 Genomes dataset. PLoS ONE 9, e97282 (2014).

    Article  Google Scholar 

  16. Nothnagel, M., Furst, R. & Rohde, K. Entropy as a measure for linkage disequilibrium over multilocus haplotype blocks. Hum. Hered. 54, 186–198 (2002).

    Article  CAS  Google Scholar 

  17. Nothnagel, M. & Rohde, K. The effect of single-nucleotide polymorphism marker selection on patterns of haplotype blocks and haplotype frequency estimates. Am. J. Hum. Genet. 77, 988–998 (2005).

    Article  CAS  Google Scholar 

  18. Kumasaka, N., Nakamura, Y. & Kamatani, N. The textile plot: a new linkage disequilibrium display of multiple–single nucleotide polymorphism genotype data. PLoS ONE 5, e10207 (2010).

    Article  Google Scholar 

  19. Weetman, A.P. Graves' disease. N. Engl. J. Med. 343, 1236–1248 (2000).

    Article  CAS  Google Scholar 

  20. Brix, T.H., Kyvik, K.O., Christensen, K. & Hegedus, L. Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts. J. Clin. Endocrinol. Metab. 86, 930–934 (2001).

    CAS  PubMed  Google Scholar 

  21. Chu, X. et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat. Genet. 43, 897–901 (2011).

    Article  CAS  Google Scholar 

  22. Zhao, S.X. et al. Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis. Hum. Mol. Genet. 22, 3347–3362 (2013).

    Article  CAS  Google Scholar 

  23. Nakabayashi, K. et al. Identification of independent risk loci for Graves' disease within the MHC in the Japanese population. J. Hum. Genet. 56, 772–778 (2011).

    Article  CAS  Google Scholar 

  24. Ueda, S. et al. Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis. J. Clin. Endocrinol. Metab. 99, E379–E383 (2014).

    Article  CAS  Google Scholar 

  25. Onuma, H., Ota, M., Sugenoya, A. & Inoko, H. Association of HLA-DPB1*0501 with early-onset Graves' disease in Japanese. Hum. Immunol. 39, 195–201 (1994).

    Article  CAS  Google Scholar 

  26. Simmonds, M.J. et al. A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect. Hum. Mol. Genet. 16, 2149–2153 (2007).

    Article  CAS  Google Scholar 

  27. Ban, Y. et al. Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves' disease. Genes Immun. 5, 203–208 (2004).

    Article  CAS  Google Scholar 

  28. Jin, H. et al. Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility. Proc. Natl. Acad. Sci. USA 111, 3787–3792 (2014).

    Article  CAS  Google Scholar 

  29. Miyadera, H. et al. Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA. J. Clin. Invest. 125, 275–291 (2015).

    Article  Google Scholar 

  30. Yamaguchi-Kabata, Y. et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am. J. Hum. Genet. 83, 445–456 (2008).

    Article  CAS  Google Scholar 

  31. Okada, Y. et al. HLA-Cw*1202-B*5201–DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn's disease. Gastroenterology 141, 864–871 (2011).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

  34. Nakajima, M. et al. A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine. Nat. Genet. 46, 1012–1016 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank N. Kumasaka who originally developed the Disentangler software. We acknowledge T. Aoi and C. Inai for technical assistance and the members of BioBank Japan and the Rotary Club of Osaka-Midosuji District 2660 Rotary International for supporting our study. Y.O. was supported by the Japan Science and Technology Agency (JST), the Japan Society of the Promotion of Science (JSPS), the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Takeda Science Foundation, the Gout Research Foundation, the Tokyo Biochemical Research Foundation and the Japan Rheumatism Foundation. The BioBank Japan Project was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government.

Author information

Authors and Affiliations

Authors

Contributions

Y.O. wrote the manuscript. Y.O., Y.K., M. Kanai and A.T. conducted the data analyses. Y.M., K.A. and M. Kubo conducted SNP and HLA genotyping. K.M. and M. Kubo collected the samples. Y.O. and M. Kubo designed the study.

Corresponding authors

Correspondence to Yukinori Okada or Michiaki Kubo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–3. (PDF 309 kb)

Supplementary Table 4

Detailed association results of the HLA variants in the MHC region on Graves' disease risk. (XLSX 1381 kb)

Supplementary Table 5

Stepwise conditional association results of the HLA amino acid positions on Graves' disease risk. (XLSX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okada, Y., Momozawa, Y., Ashikawa, K. et al. Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese. Nat Genet 47, 798–802 (2015). https://doi.org/10.1038/ng.3310

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3310

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