Abstract

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10−117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

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Acknowledgements

We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from 100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea.

This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea.

Author information

Author notes

    • Celi Sun
    • , Julio E Molineros
    • , Loren L Looger
    • , Xu-jie Zhou
    •  & Kwangwoo Kim

    These authors contributed equally to this work.

Affiliations

  1. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Celi Sun
    • , Julio E Molineros
    • , Xana Kim-Howard
    • , Prasenjeet Motghare
    • , Krishna Bhattarai
    • , Adam Adler
    • , Jonathan D Wren
    •  & Swapan K Nath
  2. Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, USA.

    • Loren L Looger
  3. Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.

    • Xu-jie Zhou
    • , Yuan-yuan Qi
    •  & Hong Zhang
  4. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

    • Kwangwoo Kim
    • , So-Young Bang
    • , Hye-Soon Lee
    • , Tae-Hwan Kim
    •  & Sang-Cheol Bae
  5. Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

    • Yukinori Okada
  6. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Yukinori Okada
  7. Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

    • Jianyang Ma
    •  & Nan Shen
  8. School of Medicine, Kyungpook National University Hospital, Daegu, Korea.

    • Young Mo Kang
  9. Department of Rheumatology, Ajou University Hospital, Suwon, Korea.

    • Chang-Hee Suh
  10. Department of Internal Medicine, Dong-A University Hospital, Busan, Korea.

    • Won Tae Chung
  11. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

    • Yong-Beom Park
  12. Department of Internal Medicine, Daegu Catholic University Hospital, Daegu, Korea.

    • Jung-Yoon Choe
  13. Daejeon Rheumatoid and Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Korea.

    • Seung Cheol Shim
  14. Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.

    • Yuta Kochi
    • , Akari Suzuki
    •  & Kazuhiko Yamamoto
  15. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Michiaki Kubo
  16. Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

    • Takayuki Sumida
  17. Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Kazuhiko Yamamoto
  18. Department of Rheumatology, Chonnam National University Hospital, Gwangju, Korea.

    • Shin-Seok Lee
  19. Korea National Institute of Health, Osong, Korea.

    • Young Jin Kim
    •  & Bok-Ghee Han
  20. Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Mikhail Dozmorov
  21. Department of Pediatrics, Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.

    • Kenneth M Kaufman
    •  & John B Harley
  22. Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Nan Shen
  23. Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

    • Kek Heng Chua

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Contributions

S.K.N., J.B.H. and S.-C.B. conceived and initiated the study. S.K.N. designed, coordinated and supervised the overall study. C.S., X.Z., P.M., K.B., A.A. and X.K.-H. prepared samples, performed genotyping, cleaned the data, combined various data sets and maintained the database. C.S., J.E.M., K.K. and Y.O. performed data imputation, association analysis and various statistical analyses on the data. L.L.L., J.E.M., M.D. and J.D.W. performed the bioinformatic analysis. S.-C.B., H.Z., K.H.C., X.Z., K.K., S.-Y.B., H.-S.L., T.-H.K., Y.M.K., C.-H.S., W.T.C., Y.-B.P., J.-Y.C., S.C.S., S.-S.L., Y.J.K., B.-G.H., Y.K., A.S., M.K., T.S., K.Y., J.M., Y.Q., K.M.K. and N.S. recruited and characterized patients with SLE and controls and supplied the demographic and clinical data. C.S., J.E.M., X.K.-H., K.K., S.-C.B., L.L.L. and S.K.N. drafted the manuscript. All authors approved the study, reviewed the manuscript, commented and helped in revising the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sang-Cheol Bae or Swapan K Nath.

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    Summary-level association data for the discovery sets.

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https://doi.org/10.1038/ng.3496

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