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GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region

Genes & Immunity volume 15, pages 347–354 (2014)Cite this article

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Abstract

In a genome-wide association study (GWAS) of individuals of European ancestry afflicted with systemic lupus erythematosus (SLE) the extensive utilization of imputation, step-wise multiple regression, lasso regularization and increasing study power by utilizing false discovery rate instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of four genes previously reported to be associated. Novel genes associated with SLE susceptibility included two transcription factors (EHF and MED1), two components of the NF-κB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6) and two genes involved in antigen presentation (BIN1 and SEC61G). In addition, the strongly significant association of multiple single-nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals. The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease.

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Acknowledgements

This work was supported by the U.S. National Institutes of Health grants: (R01AR043814 to BPT, R01AR057172 to COJ, R01AR043274 to KLS, R56AI063274, P20GM103456 to PMG, N01AR62277, R37AI024717, R01AR042460 and P20RR020143 to JBH, P01AI083194 to JBH, KLS, RPK, LAC, TJV, MEA-R, COJ, BPT and PMG, P01AR49084 to RPK, R01AR33062 to RPK, R01CA141700 and RC1AR058621 to MEA-R, P60AR053308, R01AR052300, and UL1TR000004 to LAC); the Lupus Research Institute grant to BPT; the Alliance for Lupus Research grants to BPT, LAC and COJ; the Arthritis Research UK to TJV; the Arthritis Foundation to PMG; the Kirkland Scholar Award to LAC; Wake Forest University Health Sciences Center for Public Health Genomics to CDL; Swedish Research Council to MEA-R; and Instituto de Salud Carlos III, co-financed by FEDER funds of the European Union to MEA-R. The authors would also like to specifically acknowledge the helpful suggestions of reviewer 2 to improve the analysis and paper.

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The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine, The Lupus Genetic Group, University of Southern California, Los Angeles, CA, USA

    D L Armstrong, R Zidovetzki & C O Jacob

  2. Cell Biology and Neuroscience, University of California at Riverside, Riverside, CA, USA

    D L Armstrong & R Zidovetzki

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

    M E Alarcón-Riquelme, K L Sivils & P M Gaffney

  4. Centro de Genómica e Investigación Oncológica (GENYO), Pfizer–Universidad de Granada–Junta de Andalucia, Granada, Spain

    M E Alarcón-Riquelme

  5. Division of Rheumatology, University of California Los Angeles, Los Angeles, CA, USA

    B P Tsao

  6. Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA

    L A Criswell

  7. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    R P Kimberly

  8. Division of Rheumatology and The Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    J B Harley

  9. U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, USA

    J B Harley

  10. Divisions of Genetics and Molecular Medicine and Immunology, King’s College London, London, UK

    T J Vyse

  11. Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, NC, USA

    C D Langefeld

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  1. D L Armstrong
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Correspondence to C O Jacob.

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Armstrong, D., Zidovetzki, R., Alarcón-Riquelme, M. et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun 15, 347–354 (2014). https://doi.org/10.1038/gene.2014.23

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