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Title: A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus.
Authors: Márquez, Ana
Vidal-Bralo, Laura
Rodríguez-Rodríguez, Luis
González-Gay, Miguel A
Balsa, Alejandro
González-Álvaro, Isidoro
Carreira, Patricia
Ortego-Centeno, Norberto
Ayala-Gutiérrez, María M
García-Hernández, Francisco José
González-Escribano, M Francisca
Sabio, José Mario
Tolosa, Carles
Suárez, Ana
González, Antonio
Padyukov, Leonid
Worthington, Jane
Vyse, Timothy
Alarcón-Riquelme, Marta E
Martín, Javier
Keywords: Gene Polymorphism;Rheumatoid Arthritis;Systemic Lupus Erythematosus
metadata.dc.subject.mesh: Adaptor Proteins, Vesicular Transport
Arthritis, Rheumatoid
Gene Expression Regulation
Genetic Loci
Genetic Pleiotropy
Genetic Predisposition to Disease
Genome-Wide Association Study
Lupus Erythematosus, Systemic
Polymorphism, Single Nucleotide
Protein Interaction Domains and Motifs
Issue Date: 18-May-2016
Abstract: During the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE. We performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls. The rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E-13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein-protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE. In conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.
metadata.dc.identifier.doi: 10.1136/annrheumdis-2016-209436
Appears in Collections:Producción 2020

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