Abstract

The human major histocompatibility complex (MHC) region has been shown to be associated with numerous diseases. However, it remains a challenge to pinpoint the causal variants for these associations because of the extreme complexity of the region. We thus sequenced the entire 5-Mb MHC region in 20,635 individuals of Han Chinese ancestry (10,689 controls and 9,946 patients with psoriasis) and constructed a Han-MHC database that includes both variants and HLA gene typing results of high accuracy. We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02. We anticipate that our Han-MHC reference panel built by deep sequencing of a large number of samples will serve as a useful tool for investigating the role of the MHC region in a variety of diseases and thus advance understanding of the pathogenesis of these disorders.

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Acknowledgements

We thank the faculty and staff at Anhui Medical University and BGI-Shenzhen who contributed to the Han-MHC project. We acknowledge grant support from the Key Program of the National Natural Science Foundation of China (81130031), the National Science Fund for Excellent Young Scholars (81222022), the Top-Notch Young Talents Program of China, the Pre-National Basic Research Program of China (973 plan; 2012CB722404), the National Natural Science Foundation of China (81573035, 81273301, 81271747, 81370044, 8157120504 and 81502713), the Natural Science Foundation of Anhui Province (1508085JGD05), the Program of Outstanding Talents of Anhui Medical University and the Shenzhen municipal government of China (CXZZ20140904154910774).

Author information

Author notes

    • Fusheng Zhou
    • , Hongzhi Cao
    • , Xianbo Zuo
    • , Tao Zhang
    • , Xiaoguang Zhang
    •  & Xiaomin Liu

    These authors contributed equally to this work.

Affiliations

  1. Department of Dermatology, No. 1 Hospital and Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China.

    • Fusheng Zhou
    • , Xianbo Zuo
    • , Xiaoguang Zhang
    • , Gang Chen
    • , Xiaodong Zheng
    • , Jinping Gao
    • , Yujun Sheng
    • , Bo Liang
    • , Changbing Shen
    • , Caihong Zhu
    • , Xing Fan
    • , Min Yue
    • , Xianyong Yin
    • , Cuicui Zhang
    • , Liang Yu
    • , Mengyun Chen
    • , Lili Tang
    • , Longmao Wu
    • , Yu Xu
    • , Suli Zhao
    • , Ge Li
    • , Lei Zeng
    • , Yanyan Wu
    • , Zhengwei Zhu
    • , Zaixing Wang
    • , Peiguang Wang
    • , Leihong Xiang
    • , Anping Zhang
    • , Sen Yang
    • , Jianjun Liu
    • , Liangdan Sun
    •  & Xuejun Zhang
  2. BGI-Shenzhen, Shenzhen, China.

    • Hongzhi Cao
    • , Tao Zhang
    • , Xiaomin Liu
    • , Yuanwei Zhang
    • , Xin Jin
    • , Junpu Mei
    • , Qibin Li
    • , Juan Shen
    • , Hui Jiang
    • , Fengping Xu
    • , Chen Ye
    • , Xiao Liu
    • , Jinghua Wu
    • , Xuehan Zhuang
    • , Haojing Shao
    • , Jian Li
    • , Yijie Zhang
    • , Yu Wang
    • , Hanshi Xu
    • , Jianan Wang
    • , Mingzhou Bai
    • , Yanling Chen
    • , Wei Chen
    • , Tian Kang
    • , Xun Xu
    • , Yingrui Li
    • , Huanming Yang
    • , Jian Wang
    • , Lennart Hammarström
    •  & Jun Wang
  3. iCarbonX, Shenzhen, China.

    • Hongzhi Cao
    • , Yingrui Li
    •  & Jun Wang
  4. Department of Biology, University of Copenhagen, Copenhagen, Denmark.

    • Hongzhi Cao
    • , Hui Jiang
    • , Fengping Xu
    • , Xiao Liu
    • , Jian Li
    •  & Jun Wang
  5. Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Key Laboratory of Nephrology, Ministry of Health, Guangzhou, China.

    • Ricong Xu
    •  & Xueqing Yu
  6. School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.

    • Yuanwei Zhang
  7. Department of Dermatology, China–Japan Friendship Hospital, Beijing, China.

    • Yong Cui
    •  & Xuejun Zhang
  8. Department of Dermatology, No. 2 Hospital, Anhui Medical University, Hefei, China.

    • Chunjun Yang
    •  & Xuejun Zhang
  9. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.

    • Xiang Chen
  10. Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China.

    • Xinghua Gao
  11. Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China.

    • Furen Zhang
  12. Department of Dermatology, Huashan Hospital and Collaborative Innovation Center of Complex and Severe Skin Disease, Fudan University, Shanghai, China.

    • Jinhua Xu
    •  & Xuejun Zhang
  13. Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

    • Min Zheng
  14. Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

    • Jie Zheng
  15. Department of Dermatology, Peking University People's Hospital, Beijing, China.

    • Jianzhong Zhang
  16. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

    • Yingrui Li
  17. James D. Watson Institute of Genome Sciences, Hangzhou, China.

    • Jian Wang
  18. Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.

    • Lennart Hammarström
  19. Princess Al-Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Jun Wang
  20. Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.

    • Jun Wang
  21. Department of Medicine, University of Hong Kong, Hong Kong, China.

    • Jun Wang
  22. State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China.

    • Jun Wang

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Contributions

Xuejun Zhang and Jun Wang conceived the study and designed scientific objectives. Xuejun Zhang, Jun Wang, L.S., L.H., J. Liu and X. Zuo participated in the study design. L.S. and H.C. led the project and manuscript preparation. H.C., T.Z. and Xiaomin Liu managed the project. Xiaoguang Zhang, R.X., B.L., G.C., C.S., C. Zhu, X.F., M.Y., C. Zhang, L.Y., M.C., L.T., L.W., Y.X., S.Z., G.L., L.Z., Y. Wu, Z.Z., Y. Cui, Z.W., C. Yang, P.W., L.X., X.C., A.Z., X.G., F. Zhang, J.X., M.Z., J. Zheng, J. Zhang, X. Yu and S.Y. conducted sample selection and data management, undertook recruitment, collected phenotype data, undertook related data handling and calculations, managed recruitment and obtained biological samples. H.J., F.X., Xiao Liu, J. Wu and J. Li generated the sequence data. T.Z., Xiaomin Liu, Yuanwei Zhang, X.J., J.M., Q.L., J.S., X. Zhuang, H.S., Yijie Zhang, Y. Wang, H.X., M.B., Y. Chen, W.C., H.Y., Jian Wang and C. Ye performed polymorphism analysis and constructed the Han-MHC database. F. Zhou, H.C., T.Z., Xiaoguang Zhang, Xiaomin Liu, G.C., Yuanwei Zhang, X. Zheng, J.G., Y.S., X. Yin, Jianan Wang, T.K., X.X., Y.L. and L.H. conducted the association analysis. F. Zhou, H.C., X. Zuo, T.Z., Xiaoguang Zhang and Xiaomin Liu did most of the writing with contributions from all authors. All authors contributed to the final manuscript, with Xuejun Zhang, Jun Wang, L.S., L.H., F. Zhou, H.C., X. Zuo, T.Z., Xiaoguang Zhang and Xiaomin Liu having key roles.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lennart Hammarström or Liangdan Sun or Jun Wang or Xuejun Zhang.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15, Supplementary Tables 2, 4, 6, 7 and 9 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    HLA type frequency.

  2. 2.

    Supplementary Table 3

    Selected tagging SNPs.

  3. 3.

    Supplementary Table 5

    MHC haplotype frequency.

  4. 4.

    Supplementary Table 8

    HLA types from sequencing data and the 1000 Genomes Project.

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DOI

https://doi.org/10.1038/ng.3576

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