Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus

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.

Keywords: Biological pathway analysis; Genetic susceptibility; Genome-wide association study; Meta-analysis; Systemic lupus erythematosus.

Fig. 1

Manhattan plot of genome-wide association study meta-analysis results including the Spain cohort. Plot of the -log10 (p values) of association between the 7,110,321 markers after meta-analysis between the European and Spain cohorts. The dashed horizontal line represents the genome-wide significance threshold (p value = 5 × 10^− 8). The known regions associated with systemic lupus erythematosus (SLE) risk and genome-wide significant are colored in red. The five new genomic regions associated with SLE risk in this study are colored in green, with the name of the corresponding gene above

Fig. 2

Regional association plots from the meta-analysis of the two cohorts for all five genome-wide significant loci: -log10 (p values) for both directly genotyped and imputed single nucleotide polymorphisms (SNPs) are plotted as a function of genomic position (NCBI Build 37). The purple diamond indicates the lead SNP at each locus; the remaining markers are colored based on the LD (r [2]) in relation to the lead SNP. Underlying the image, the estimated recombination rate (cM/Mb) for the CEU panel from 1000 Genomes is depicted