Journal Article

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

Fernández-Nebro, Antonio, Julià, Antonio, Blanco, Ricardo, Marsal, Sara, Andreu, José Luís, Zea, Antonio, López-Longo, Francisco Javier, Torrents, David, Díez, Elvira, Mercader, Josep M., Aguirre-Zamorano, Mª. Ángeles, Pérez Venegas, José J., Carreira, Patricia, Bonàs-Guarch, Silvia, Corbeto, Mireia López, López-Lasanta, María, Nolla, Joan M., Freire, Mercedes, Olivé, Àlex, Vela, Paloma, Pego-Reigosa, José María, Rodríguez-Almaraz, Esther, Absher, Devin, Taboada, Víctor Martínez, de la Fuente, José Luís Marenco

2018

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Arthritis / Autoimmune diseases / Biological pathway analysis / Biology / Cancer / Cohort Studies / Consortia / Disease / DNA methylation / Gene expression / Genealogy / Genetic aspects / Genetic Loci - genetics / Genetic research / Genetic susceptibility / Genetic Variation - genetics / Genome-wide association study / Genome-Wide Association Study - methods / Genomes / Genomics / Health aspects / Humans / Identification and classification / Inflammatory diseases / Lupus / Lupus Erythematosus, Systemic - diagnosis / Lupus Erythematosus, Systemic - genetics / Medicine / Medicine & Public Health / Meta-analysis / Orthopedics / Population / Quality control / Quantitative trait loci / Research Article / Rheumatoid arthritis / Rheumatology / Risk factors / Software / Systemic lupus erythematosus / White people