Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

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T.J.V., J.D.R. and M.E.A.-R. were awarded funding to carry out genotyping and analysis from the George Koukis Foundation and an Arthritis Research UK Special Strategic Award (19289). M.E.A.-R. received grants from the Instituto de Salud Carlos III (PS09/00129), co-financed by the FEDER funds of the European Union, the Consejería de Salud de Andalucía (PI0012) and the Swedish Research Council of Medicine, and from the European Science Foundation to the BIOLUPUS network. J.B. was funded by the George Koukis Foundation and the Arthritis Research UK Special Strategic Award. J.E.W. was funded by the Canadian Institutes of Health Research (94825). C.L.P. was funded by a Wellcome Trust grant (085492). P.T. is employed by the Biomedical Research Centre. L.C. was funded by the China Scholarship Council (201406380127). The research was funded and supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health.

HRS genetic data were obtained from the database of Genotypes and Phenotypes (dbGaP) under accession phs000187.v1.p1; the study is sponsored by the National Institute on Aging (grants U01AG009740, RC2AG036495 and RC4AG039029) and was conducted by the University of Michigan. The melanoma study data were obtained from dbGaP under accession phs000187.v1.p1. Research support to collect data and develop an application to support this project was provided by US National Institutes of Health (NIH) grants 3P50CA093459, 5P50CA097007, 5R01ES011740 and 5R01CA133996. Funding support for the Genes and Blood Clotting Study was provided through the US NIH/National Heart, Lung, and Blood Institute (NHLBI) (R37HL039693). The Genes and Blood Clotting Study is one of the Phase 3 studies that are part of the Gene-Environment Association Studies (GENEVA) under the Genes, Environment and Health Initiative (GEI). Assistance with genotype cleaning was provided by the GENEVA Coordinating Center (U01HG004446, US NIH). Funding support for DNA extraction and genotyping, which were performed at the Broad Institute, was provided by the US NIH/NHLBI (R37HL039693). Additional support was provided by the Howard Hughes Medical Institute. The data sets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000304.v2.p1. CGEMS prostate cancer study data were obtained from dbGaP under accession phs000207.v1.p1. We thank Genentech, Inc., for providing the genotype data from their GWAS. We thank V. Anand and S. Ragan for their help in coordinating data collection. We thank T. Axelsson, B. Fürnrohr, S. Ragan and J. Kelly for their help with the replication study.

A large number of people contributed samples or clinical data to the GWAS. The following samples were obtained via the BIOLUPUS network coordinated by M.E.A.-R.: Belgium: B. Lawerys and F. Houssiau (Université Catholique de Louvain). Denmark: S. Jacobsen (University of Copenhagen), P. Junker and H. Laustrup (Odense University Hospital). Germany: T. Witte (Medizinische Hochschule Hannover). Greece: H. Moutsopoulos and E.K. Kapsogeorgou (National University of Athens). Hungary: E. Endreffy and L. Kovacs (Albert Szent-Györgyi Medical University). Iceland: K. Steinsson (Landspitali National University Hospital). Italy: A. Doria (University of Padova), P.L. Meroni (IRCCS Istituto Auxologico Italiano), R. Scorza (University of Milan), S. D'Alfonso (providing samples from Rome, Naples and Siena; Università del Piemonte Orientale). The Netherlands: M. Bijl and C. Kallenberg (University of Groningen). Portugal: C. Vasconcelos (Hospital Santo António, Porto), B. Martins Silva (University of Porto). Spain: J. Martín and E. Martín Rodríguez (Instituto de Parasitología y Biomedicina Lopez Neyra), A. Suárez (Hospital Universitario Central de Asturias), I. Rua Figueroa (Hospital Dr. Negrín, Gran Canaria), G. Pons-Estel (Hospital Clinic, Barcelona). From the GENLES collaboration: Argentina: B. Pons-Estel (Hospital Provincial de Rosario). Other contributors: Canada: P. Fortin, J. Wither, D. Gladman and M. Urowitz (Toronto Western Hospital, University Health Network), A. Clarke, S. Bernatsky, C. Pineau and J. Rauch (McGill University), T. Hudson (Ontario Institute for Cancer Research), J. Pope (University of Western Ontario), C. Peschken and C. Hitchon (University of Manitoba), J. Hanly (Dalhousie University), C.D. Smith (Ottawa Hospital), E. Rich and J.-L. Senécal (Centre Hospitalier de l'Université de Montréal), M. Zummer (Maisonneuve-Rosemont Hospital), G. Boire (Université de Sherbrooke), S. Barr (University of Calgary). Germany: M.-A. Lee-Kirsch (Technische Universität Dresden). The Netherlands: T. Huizinga (Leiden University Medical Center; Dutch and Polish samples). Spain: J. Cortés Hernández, J. Ordi Ros and J. Castro Marrero (Vall d'Hebron Research Institute). Turkey: S. Yavuz (Istanbul Bilim University, Avrupa Florence Nightingale Hospital). UK: C. Gordon (University of Birmingham), K. Vinen (King's College London), D. Isenberg (University College Hospital), L. Erwig (University of Aberdeen), D. D'Cruz (St. Thomas' Hospital, London), A.J. Rees (Medical Research Council/Kidney Research UK Glomerulonephritis Biobank), I. Bruce (University of Manchester). United States: A. Sawalha (University of Michigan; Turkish samples), L. Criswell (University of California, San Francisco).

For the replication study, samples were provided by J. Wither (Toronto Western Research Institute, University Health Network, Canada), E. Silverman (The Hospital for Sick Children and University of Toronto, Canada), P. Gaffney (Oklahoma Medical Research Foundation, USA), A.-C. Syvänen and L. Rönnblom and the Swedish SLE Network (Uppsala Universitet, Sweden), R. Voll, G. Schett and B. Fuernrohr (University of Erlangen-Nuremberg, Germany) and N. Costedoat-Chalumeau (AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, France; Université Paris Descartes–Sorbonne Paris Cité, France). Replication genotyping was performed by the SNP&SEQ Technology Platform in Uppsala, which is part of the Swedish National Genomics Infrastructure (NGI) hosted by the Science for Life Laboratory.

We thank T. Raj and P. De Jager for contributing gene expression data (CD4+ T cells and CD14+ or CD16+ monocytes). These gene expression data are deposited in the Gene Expression Omnibus under accession GSE56035.

Author information

Author notes

    • James Bentham

    Present address: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • James Bentham
    •  & David L Morris

    These authors contributed equally to this work.


  1. Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • James Bentham
    • , David L Morris
    • , Deborah S Cunninghame Graham
    • , Christopher L Pinder
    • , Philip Tombleson
    • , Lingyan Chen
    •  & Timothy J Vyse
  2. Genentech, Inc., South San Francisco, California, USA.

    • Timothy W Behrens
    •  & Robert R Graham
  3. Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.

    • Javier Martín
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Benjamin P Fairfax
    •  & Julian C Knight
  5. Harvard Medical School, Boston, Massachusetts, USA.

    • Joseph Replogle
  6. Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Ann-Christine Syvänen
    •  & Lars Rönnblom
  7. Toronto Western Research Institute (TWRI), University Health Network, Toronto, Ontario, Canada.

    • Joan E Wither
  8. Genetics and Genomic Medicine of Inflammation, Université de Montréal, Montreal, Quebec, Canada.

    • John D Rioux
  9. Montreal Heart Institute, Montreal, Quebec, Canada.

    • John D Rioux
  10. Centro de Genómica e Investigación Oncológica (GENYO), Pfizer–Universidad de Granada–Junta de Andalucía, Granada, Spain.

    • Marta E Alarcón-Riquelme
  11. Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.

    • Timothy J Vyse


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T.J.V. supervised the study. M.E.A.-R., J.M., A.-C.S., L.R. and J.E.W. provided samples. J.B. preprocessed the genotype data and carried out quality control analysis for the GWAS data. D.L.M., P.T. and J.B. carried out statistical analysis of the GWAS data. D.L.M. and T.J.V. designed the replication chip. D.L.M., P.T. and J.B. carried out quality control analysis of the controls for the replication study. T.W.B. and R.R.G. provided data from an SLE GWAS that were used in the meta-analysis. D.L.M. carried out statistical analysis for the replication study. D.L.M. and J.B. carried out statistical analysis of the 1000 Genomes Project data. D.L.M., L.C., J.R., B.P.F. and J.C.K. carried out statistical analysis of the eQTL data. D.S.C.G. and C.L.P. coordinated sample collection and genotyping. D.L.M., J.B., D.S.C.G., J.D.R. and T.J.V. wrote the manuscript. All authors have read and contributed to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy J Vyse.

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