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

Abstract

BackgroundSystemic 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.MethodsWe 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.ResultsWe 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).ConclusionsOur results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1604-1) contains supplementary material, which is available to authorized users.

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

“…Up to 100 susceptibility loci for polygenic, multifactorial SLE and more than 30 genes causing the monogenic form of SLE and SLE-like phenotypes have been described, yet they capture only a small proportion of heritability to lupus and other autoimmune diseases (Table 1) [1][2][3][4][5][6]. Discovery of novel or rare disease-causing gene variants in patients with early-onset SLE phenotype has had a significant contribution to the unraveling of molecular pathways involved in the disease pathogenesis [7][8][9].…”

An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus

“…Furthermore, we also identified significant lower expression of CD79A and CD79B (also known as Igα and Igβ, respectively). In a meta-analysis of GWAS results, Julià et al reported BCR signaling pathway as the most significant biological process and BCL10 and CD79A among top single markers associated with SLE [57]. Fig.…”

<p>Towards Precision Medicine in Systemic Lupus Erythematosus</p>

“…51 Some studies demonstrate that pathological elevation of these cytokines induce neurological dysfunctions (mainly in mouse models). NPLE CSF studies indicate INFα and IL6 as possibly related to CNS diffuse damage 52,53 .…”

“…Although a strong genetic association was always evident, little was known of SLE genetics until the development of the genome wide association studies (GWAS). 54,55 These studies are hypothesis-free genome screening that link gene loci with disease phenotype in multifactorial diseases, as SLE. Prior to GWAS, a few genes were known to be associated to SLE, as is the case of the human leukocyte antigen (HLA) haplotypes.…”