Abstract

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype–phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes.

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Code availability

Software and codes used for this study are available from URLs or upon request to the authors.

Data availability

HLA data have been deposited at the National Bioscience Database Center (NBDC) Human Database (research ID: hum0114) as open data without any access restrictions. GWAS data and phenotype data of the BBJ individuals are available at the NBDC Human Database (research ID: hum0014).

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

We thank T. Aoi for kind support of the study. This research was supported by the Tailor-Made Medical Treatment program (the BioBank Japan Project) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED), MEXT KAKENHI (221S0002), Bioinformatics Initiative of Osaka University Graduate School of Medicine, and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University. Y.O. was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15H05670, 15H05911 and 15K14429), AMED (18gm6010001h0003 and 18ek0410041h0002), Takeda Science Foundation, the Uehara Memorial Foundation, the Naito Foundation, Daiichi Sankyo Foundation of Life Science, Senri Life Science Foundation and Suzuken Memorial Foundation. K.H. was supported by JSPS KAKENHI grant no. P16H06502 ‘Neo-self’. J.H. is an employee of Teijin Pharma Limited. Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics.

Author information

Affiliations

  1. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

    • Jun Hirata
    • , Saori Sakaue
    • , Masahiro Kanai
    • , Ken Suzuki
    • , Toshihiro Kishikawa
    • , Kotaro Ogawa
    • , Tatsuo Masuda
    • , Kenichi Yamamoto
    •  & Yukinori Okada
  2. Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Hino, Japan

    • Jun Hirata
  3. Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa, Japan

    • Kazuyoshi Hosomichi
  4. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Saori Sakaue
    • , Masahiro Kanai
    • , Kazuyoshi Ishigaki
    • , Ken Suzuki
    • , Masato Akiyama
    • , Yoichiro Kamatani
    •  & Yukinori Okada
  5. Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

    • Saori Sakaue
  6. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    • Masahiro Kanai
  7. Division of Human Genetics, National Institute of Genetics, Shizuoka, Japan

    • Hirofumi Nakaoka
    •  & Ituro Inoue
  8. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    • Ken Suzuki
  9. Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan

    • Masato Akiyama
  10. Department of Otorhinolaryngology, Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    • Toshihiro Kishikawa
  11. Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan

    • Kotaro Ogawa
  12. Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan

    • Tatsuo Masuda
  13. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan

    • Kenichi Yamamoto
  14. Laboratory of Genome Technology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    • Makoto Hirata
  15. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    • Koichi Matsuda
  16. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Yukihide Momozawa
  17. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Michiaki Kubo
  18. Kyoto-McGill International Collaborative School in Genomic Medicine, Sakyo-ku, Kyoto, Japan

    • Yoichiro Kamatani
  19. Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan

    • Yukinori Okada

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Contributions

Y.O. supervised the study. J.H., K.H., Y.K. and Y.O. wrote the manuscript. J.H., K.H., S.S., M. Kanai, K.I., K.S., M.A., T.K., K.O., T.M., K.Y., Y.K. and Y.O. conducted data analysis. M.H., K.M., M. Kubo and Y.K. provided data. Y.O., K.M. and M. Kubo collected samples. Y.O., K.H., H.N., Y.M. and I.I. conducted experiments.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Yukinori Okada.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Tables 1, 2 and 4–7, and Supplementary Figures 1–3

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 3 and 8

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DOI

https://doi.org/10.1038/s41588-018-0336-0