Abstract: Background: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex
genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant
loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability
and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to
identify new genome-wide significant loci for SLE.
Methods: We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and
performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression
with correction for the principal components of variation. Meta-analysis of the association results was subsequently
performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959
controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing
the effect of known risk loci using PASCAL software.
Results: We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10? 8): GRB2,
SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated
with SLE risk: B cell receptor signaling (p = 5.28 × 10? 6), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10? 5),
interleukin-4 signaling (p = 3.97 × 10? 5) and cell surface interactions at the vascular wall (p = 4.63 × 10? 5).
Conclusions: Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple
low-effect-size loci.