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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.

Original publication

DOI

10.1038/ng.3434

Type

Journal article

Journal

Nat Genet

Publication Date

12/2015

Volume

47

Pages

1457 - 1464

Keywords

Adaptive Immunity, Case-Control Studies, Gene Expression Regulation, Genetic Association Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Humans, Immunity, Innate, Lupus Erythematosus, Systemic, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors