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Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

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James Bentham, David L. Morris, Deborah S. Cunninghame Graham, Christopher L. Pinder, Philip Tombleson, Timothy W. Behrens, Javier Martín, Benjamin P. Fairfax, Julian C. Knight, Lingyan Chen, Joseph Replogle, Ann Christine Syvänen, Lars Rönnblom, Robert R. Graham, Joan E. Wither, John D. Rioux, Marta E. Alarcón-Riquelme, Timothy Vyse

Original languageEnglish
Pages (from-to)1457-1464
Number of pages8
JournalNature Genetics
Issue number12
Early online date26 Oct 2015
Accepted/In press2 Oct 2015
E-pub ahead of print26 Oct 2015
Published1 Dec 2015


King's Authors


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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