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

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• dc.contributor.author Julià, Antonio
• dc.contributor.author Bonàs-Guarch, Silvia
• dc.contributor.author Mercader Bigas, Josep Maria
• dc.contributor.author Torrents, David
• dc.contributor.author Fernández-Nebro, Antonio
• dc.date.accessioned 2019-03-25T08:35:42Z
• dc.date.available 2019-03-25T08:35:42Z
• dc.date.issued 2018
• dc.description.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.
• dc.description.sponsorship This study was funded by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). This work has been also sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III. Sílvia Bonàs was awarded an FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya).
• dc.format.mimetype application/pdf
• dc.identifier.citation Julià A, López-Longo FJ, Pérez Venegas JJ, Bonàs-Guarch S, Olivé À, Andreu JL et al. Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus. Arthritis Res Ther. 2018; 20(1):100. DOI 10.1186/s13075-018-1604-1
• dc.identifier.doi http://dx.doi.org/10.1186/s13075-018-1604-1
• dc.identifier.issn 1478-6354
• dc.identifier.uri http://hdl.handle.net/10230/36952
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Arthritis Res Ther. 2018; 20(1):100
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SEV-2011-00067
• dc.rights © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Systemic lupus erythematosus
• dc.subject.keyword Genetic susceptibility
• dc.subject.keyword Genome-wide association study
• dc.subject.keyword Meta-analysis
• dc.subject.keyword Biological pathway analysis
• dc.title Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion