title: A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, Spain.|Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Márquez
authors.affiliation: Laboratorio de Investigación 10 and Rheumatology Unit, Instituto de Investigación Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal-Bralo
authors.affiliation: Rheumatology Department and Heath Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.affiliation: Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
authors.affiliation: Department of Rheumatology and Institute for Health Research (IdiPAZ), University Hospital La Paz, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.affiliation: Rheumatology Service and Health Research Institute (IP), Hospital Universitario de La Princesa, Madrid, Spain.
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.affiliation: Rheumatology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Carreira
authors.affiliation: Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain.
authors.forename: Norberto
authors.initials: N
authors.lastname: Ortego-Centeno
authors.affiliation: Department of Internal Medicine, Hospital Carlos Haya, Málaga, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Ayala-Gutiérrez
authors.affiliation: Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: García-Hernández
authors.affiliation: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, Spain.
authors.forename: M Francisca
authors.initials: MF
authors.lastname: González-Escribano
authors.affiliation: Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain.
authors.forename: José Mario
authors.initials: JM
authors.lastname: Sabio
authors.affiliation: Department of Internal Medicine, Hospital Parc Taulí, Sabadell, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Tolosa
authors.affiliation: Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Suárez
authors.affiliation: Laboratorio de Investigación 10 and Rheumatology Unit, Instituto de Investigación Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: González
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.|Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Vyse
authors.affiliation: Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain.|Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D058685:Genetic Pleiotropy / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C553748:COG6 protein, human
keywords: Gene Polymorphism; Rheumatoid Arthritis; Systemic Lupus Erythematosus