Objective Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.
Methods We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.
Results Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.
Conclusions We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.
- gene polymorphism
- autoimmune diseases
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MA-H and MK are joint first authors.
MA-H and JM contributed equally.
Handling editor Josef S Smolen
Collaborators Myositis Genetics Consortium: (1) Frederick W Miller; (2) Wei Chen; (1) Terrance P O’Hanlon; (3) Robert G Cooper; (4) Jiri Vencovsky; (1) Lisa G Rider; (5) Katalin Danko; (6) Lucy R Wedderburn; (7) Ingrid E. Lundberg; (8) Lauren M Pachman; (9) Ann M. Reed; (9) Steven R Ytterberg; (10) Albert Selva-O’Callaghan; (11) Timothy R Radstake; (12) David A Isenberg; (13) Hector Chinoy; (14) William E R Ollier; (2) Paul Scheet; (2) Bo Peng; (15) Annette Lee; (14) Janine A Lamb; (16) Christopher I Amos; (17) Christopher Denton; (18) David Hilton-Jones; (19) Paul H Plotz; (20) Hemlata Varsani. (1) National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA; (2) MD Anderson Cancer Center, Houston, Texas, USA; (3) MRC/ARUK Institute for Ageing and Chronic Disease, University of Liverpool, UK; (4) Institute of Rheumatology, Charles University, Prague, Czech Republic; (5) 3rd Department of Internal Medicine, Division of Immunology University of Debrecen, Debrecen, Hungary; (6) Institute of Child Health, University College London, London, UK; (7) Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden; (8) Department of Pediatric Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; (9) Mayo Clinic, Rochester, Minnesota, USA; (10) Vall d'Hebron General Hospital, Barcelona, Spain; (11) Department of Rheumatology and Clinical Immunology, Laboratory for Translational Immunology, Utrecht University Medical Center; and Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands; (12) Division of Medicine, University College London, London, UK; (13) The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK; (14) Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; (15) Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA; (16) Department of Community and Family Medicine, Dartmouth College, Hanover, NH, USA; (17) Centre for Rheumatology, Royal Free Hospital, London, UK; (18) Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; (19) National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA; (20) University College London, London, UK.
Scleroderma Genetics Consortium: Timothy R.D.J. Radstake,1Olga Gorlova,2 Blanca Rueda,3 Jose-Ezequiel Martin,3Behrooz Z. Alizadeh,4 Rogelio Palomino-Morales,3Marieke J. Coenen,5 Madelon C. Vonk,1 Alexandre E.Voskuyl,6 Annemie J. Scheurwegh,7 Jasper C. Broen,1Piet L.C.M. van Riel,1 Ruben van ‘t Slot,4 AnnetItaliaander,4 Roel A. Ophoff,4,8 Gabriela Riemekasten,9Nico Hunzelmann,10 Carmen P. Simeon,11 NorbertoOrtego-Centeno,12 Miguel A. González-Gay,13 María F.González-Escribano,14 Paolo Airo,15 Jaap van Laar,16Ariane Herrick,17 Roger Hesselstrand,18 Vanessa Smith,19Filip de Keyser,19 Fredric Houssiau,20 Meng May Chee,21Rajan Madhok,21 Paul Shiels,21 Rene Westhovens,22Alexander Kreuter,23 Hans Kiener,24 Elfride de Baere,25Torsten Witte,26 Lars Klareskog,27 Lorenzo Beretta,28Rafaella Scorza,28 Benedicte A. Lie,29 Anna-MariaHoffman-Vold,30 Patricia Carreira,31 John Varga,32Monique Hinchcliff,32 Annette T. Lee,32 Jun Ying,2Younghun Han,2 Shih-Feng Weng,2 Fredrick M. Wigley,33Laura Hummers,33 J. Lee Nelson,34 Sandeep K. Agarwal,35Shervin Assassi,35 Pravitt Gourh,35 Filemon K. Tan,35Bobby P.C. Koeleman,4 Frank C Arnett.35
1Radboud University NijmegenMedical Center, Department of Rheumatology, The Netherlands; 2Departmentof Epidemiology, M.D. Anderson Cancer Center, Houston, TX, USA; 3Instituto de Parasitologíay Biomedicina López-Neyra, CSIC, Granada, Spain; 4Department of MedicalGenetics, University Medical Center Utrecht, The Netherlands; 5RadboudUniversity Nijmegen Medical Center, Department of Human Genetics, TheNetherlands; 6Department of Rheumatology, VU University MedicalCentre, Netherlands; 7Department of Rheumatology, University ofLeiden, The Netherlands; 8UCLA Center for Neurobehavioral Genetics,Los Angeles, California; 9Department of Rheumatology and ClinicalImmunology, Charité University Hospital, Berlin, Germany; 10Departmentof Dermatology, University of Cologne, Germany; 11Servicio deMedicina Interna, Hospital Valle de Hebron, Barcelona, Spain; 12Serviciode Medicina Interna, Hospital Clínico Universitario, Granada, Spain; 13Serviciode Reumatología, Hospital Marqués de Valdecilla, Santander, Spain; 14Serviciode Inmunología, Hospital Virgen del Rocío, Sevilla, Spain; 15Universityof Brecia, Italy; 16University of Newcastle, United Kingdom; 17Universityof Manchester, United Kingdom; 18University of Lund, Sweden; 19Universityof Ghent, Belgium; 20University of Leuven, Belgium; 21Universityof Glasgow, United Kingdom; 22University of Antwerpen, Belgium; 23RuhrUniversity of Bochum, Germany; 24University of Vienna, Austria; 25Departmentof Genetics, University of Ghent, Belgium; 26University of Hannover,Hannover, Germany; 27Karolinska Institute, Stockholm, Sweden; 28Universityof Milan, Italy; 29Institute of Immunology, Rikshospitalet, OsloUniversity Hospital, Oslo, Norway; 30Department of Rheumatology,Rikshospitalet, Oslo University Hospital, Oslo, Norway; 31Hospital12 de Octubre, Madrid; 32Feinstein Institute of Medical Research,Manhasset, NY, USA; 33Johns Hopkins University Medical Center,Baltimore, MD, USA; 34Fred Hutchinson Cancer Research Center,Seattle, WA, USA; 35The University of Texas Health ScienceCenter-Houston, Houston, TX, USA.
Contributors Data providers: FWM, WC, TPO, RGC, JV, LGR, KD, LRW, IEL, LMP, AMR, SRY, ASO, TRR, DAI, HC, WERO, PS, BP, AL,JAL, CIA, CD, DHJ, PP, HV, on behalf of the Myositis Genetics Consortium; OG, BR, JEM, BZA, RPM, MJC, MCV, AEV, AJS, JCB, PLCMR, RS, AI, RAO, GR, NH, CPS, NOC, MAGG, MGE, PA, JVL, AH, RH, VS, FDK, FH, MMC, RM, PS, RW, AK, HK, EDB, TW, LK, LB, RS, BAL, AMHV, PC, JV, MH, ATL, JY, YH, SFW, FMW, LH, JLN, SKA, SA, PG, FKT, BPCK, FCA, on behalf of the Scleroderma Genetics Consortium; QC and imputation in the contributing studies: MAH, MK, DGS; Functional and drug enrichment analysis: MAH, MK; Meta-analysis, tables and figures: MAH, MK, DGS; Drafting and approved version of the manuscript: MAH, MK, DGS,CW, AF, PKG, LP, JW, TV, MEAR, MDM, JM, FWM, WC,TPO, RGC, JV, LGR, KD, LRW, IEL, LMP, AMR, SRY, ASO, TRR, DAI, HC, WERO, PS, BP, AL, JAL, CIA, CD, DHJ, PP, HV; Study design and management: MAH, MK, JM.
Funding Funded by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (115565), The Spanish Ministry of Economy Industry and Competitiveness (SAF2015-66761-P), The Regional Ministry of Innovation, Science and Technologies of the Andalusian Regional Government (P12-BIO-1395) and Juan de la Cierva fellowship (FJCI-2015-24028). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was conducted using available data included in previously published GWAS (online supplementary references 1–6).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Summary statistics of the global meta-analysis generated and analysed in the current study are available from the corresponding author on reasonable request.