Ana Márquez1,2, Laura Vidal-Bralo3, Luis Rodríguez-Rodríguez4, Miguel A González-Gay5, Alejandro Balsa6, Isidoro González-Álvaro7, Patricia Carreira8, Norberto Ortego-Centeno2, María M Ayala-Gutiérrez9, Francisco José García-Hernández10, M Francisca González-Escribano11, José Mario Sabio12, Carles Tolosa13, Ana Suárez14, Antonio González3, Leonid Padyukov15, Jane Worthington16, Timothy Vyse17,18, Marta E Alarcón-Riquelme19,20, Javier Martín1. 1. Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, Spain. 2. Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain. 3. Laboratorio de Investigación 10 and Rheumatology Unit, Instituto de Investigación Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. 4. Rheumatology Department and Heath Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain. 5. Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. 6. Department of Rheumatology and Institute for Health Research (IdiPAZ), University Hospital La Paz, Madrid, Spain. 7. Rheumatology Service and Health Research Institute (IP), Hospital Universitario de La Princesa, Madrid, Spain. 8. Rheumatology Department, Hospital 12 de Octubre, Madrid, Spain. 9. Department of Internal Medicine, Hospital Carlos Haya, Málaga, Spain. 10. Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 11. Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, Spain. 12. Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain. 13. Department of Internal Medicine, Hospital Parc Taulí, Sabadell, Spain. 14. Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain. 15. Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 16. 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. 17. Division of Genetics and Molecular Medicine, King's College London, London, UK. 18. Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK. 19. Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain. 20. Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Abstract
OBJECTIVES: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVES: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Laura A McIntosh; Miranda C Marion; Marc Sudman; Mary E Comeau; Mara L Becker; John F Bohnsack; Tasha E Fingerlin; Thomas A Griffin; J Peter Haas; Daniel J Lovell; Lisa A Maier; Peter A Nigrovic; Sampath Prahalad; Marilynn Punaro; Carlos D Rosé; Carol A Wallace; Carol A Wise; Halima Moncrieffe; Timothy D Howard; Carl D Langefeld; Susan D Thompson Journal: Arthritis Rheumatol Date: 2017-10-12 Impact factor: 10.995
Authors: Manuel A R Ferreira; Riddhima Mathur; Judith M Vonk; Agnieszka Szwajda; Ben Brumpton; Raquel Granell; Bronwyn K Brew; Vilhelmina Ullemar; Yi Lu; Yunxuan Jiang; Patrik K E Magnusson; Robert Karlsson; David A Hinds; Lavinia Paternoster; Gerard H Koppelman; Catarina Almqvist Journal: Am J Hum Genet Date: 2019-03-28 Impact factor: 11.025
Authors: Guillermo Barturen; Lorenzo Beretta; Ricard Cervera; Ronald Van Vollenhoven; Marta E Alarcón-Riquelme Journal: Nat Rev Rheumatol Date: 2018-01-24 Impact factor: 20.543
Authors: Lucie Abeler-Dörner; Adam G Laing; Anna Lorenc; Dmitry S Ushakov; Simon Clare; Anneliese O Speak; Maria A Duque-Correa; Jacqueline K White; Ramiro Ramirez-Solis; Namita Saran; Katherine R Bull; Belén Morón; Jua Iwasaki; Philippa R Barton; Susana Caetano; Keng I Hng; Emma Cambridge; Simon Forman; Tanya L Crockford; Mark Griffiths; Leanne Kane; Katherine Harcourt; Cordelia Brandt; George Notley; Kolawole O Babalola; Jonathan Warren; Jeremy C Mason; Amrutha Meeniga; Natasha A Karp; David Melvin; Eleanor Cawthorne; Brian Weinrick; Albina Rahim; Sibyl Drissler; Justin Meskas; Alice Yue; Markus Lux; George X Song-Zhao; Anna Chan; Carmen Ballesteros Reviriego; Johannes Abeler; Heather Wilson; Agnieszka Przemska-Kosicka; Matthew Edmans; Natasha Strevens; Markus Pasztorek; Terrence F Meehan; Fiona Powrie; Ryan Brinkman; Gordon Dougan; William Jacobs; Clare M Lloyd; Richard J Cornall; Kevin J Maloy; Richard K Grencis; Gillian M Griffiths; David J Adams; Adrian C Hayday Journal: Nat Immunol Date: 2019-12-16 Impact factor: 25.606
Authors: Marialbert Acosta-Herrera; Javier Martin; Martin Kerick; David González-Serna; Cisca Wijmenga; Andre Franke; Peter K Gregersen; Leonid Padyukov; Jane Worthington; Timothy James Vyse; Marta Eugenia Alarcón-Riquelme; Maureen D Mayes Journal: Ann Rheum Dis Date: 2018-12-20 Impact factor: 19.103
Authors: Lourdes Ortiz-Fernández; Francisco David Carmona; Raquel López-Mejías; Maria Francisca González-Escribano; Paul A Lyons; Ann W Morgan; Amr H Sawalha; Peter A Merkel; Kenneth G C Smith; Miguel A González-Gay; Javier Martín Journal: Ann Rheum Dis Date: 2018-01-27 Impact factor: 19.103