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High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Nature Genetics volume 48, pages 323–330 (2016)Cite this article

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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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Figure 1: Flowchart of our experimental design.
Figure 2: Manhattan plot of the meta-analysis results using the discovery sets.
Figure 3: Meta-analysis of the lead SNPs from the ten newly identified loci.
Figure 4: Cell type–specific gene expression analysis of SLE susceptibility loci.

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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

  1. Celi Sun, Julio E Molineros, Loren L Looger, Xu-jie Zhou and Kwangwoo Kim: These authors contributed equally to this work.

Authors and 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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  1. Celi Sun
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  2. Julio E Molineros
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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.

Corresponding authors

Correspondence to Sang-Cheol Bae or Swapan K Nath.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16 and Supplementary Note. (PDF 11732 kb)

Supplementary Tables 1–29

Supplementary Tables 1–29. (XLSX 2075 kb)

Supplementary Data Set

Summary-level association data for the discovery sets. (XLSX 18647 kb)

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Sun, C., Molineros, J., Looger, L. et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet 48, 323–330 (2016). https://doi.org/10.1038/ng.3496

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

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