A trans-ethnic genome-wide association study of 21,483 cases and 97,977 controls identifies 27 genetic susceptibility variants for atopic dermatitis. L. Paternoster1, M. Standl2, H. Baurecht3,4, J. Waage5, M. Hotze3, J. A. Curtin6, K. Bĝnnelykke5, D. Glass7, D. A. Hinds8, E. Melen9, P. Sleiman10, B. Feenstra11, M. Pino-Yanes12, H. T. den Dekker13, M. Bustamante14, I. Marenholz15, B. Jacobsson16,17, A. D. Irvine18, A. C. Alves19, M. M. Groen-Blokhuis20, A. Franke21, M. Ferreira22, M. Tamari23, N. Probst-Hensch24, K. Williams25, D. P. Strachan26, S. J. Brown27, J. Heinrich2, D. M. Evans1,28, S. Weidinger3 on behalf of the EAGLE Eczema Consortium 1) MRC IEU, University of Bristol, Bristol, UK; 2) Institue of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; 3) Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 4) Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany; 5) Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Denmark; 6) Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK; 7) Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK; 8) 23andMe, Inc., Mountain View, California, USA; 9) Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 10) The Center for Applied Genomics, The Childrens Hospital of Philadelphia, Philadelphia, Pensylvania, USA; 11) Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 12) Department of Medicine, University of California, San Francisco, California, USA; 13) The Generation R Study Group; Department of Pediatrics, division of Respiratory Medicine; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; 14) Center for Research in Environmental Epidemiology (CREAL), Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 15) Experimental Clinical Research Center, Charité Medical Faculty and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; 16) Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway; 17) Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, Göteburg University, Göteburg, Sweden; 18) Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; Clinical Medicine, Trinity College Dublin, Dublin, Ireland; 19) Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; 20) Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; 21) Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; 22) Queensland Institute of Medical Research Berghofer, Brisbane, Queensland, Australia; 23) Laboratory for Respiratory Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan; 24) Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute Swiss TPH, Basel, Switzerland; University of Basel, Basel, Switzerland; 25) Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA; Department of Medicine, Henry Ford Health System, Detroit, MI, USA; 26) Population Health Research Institute, St George's, University of London, London, UK; 27) Dermatology and Genetic Medicine, Medical Research Institute, University of Dundee, Dundee, UK; 28) University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Australia.

   Atopic dermatitis (AD) is a highly heritable common chronic-inflammatory skin disease. Previous genome-wide association studies (GWAS) have identified 19 associated loci. The largest previous GWAS involved around 5,000 cases and 20,000 controls, included only Europeans and identified 3 associated loci. This puts AD some way behind many other complex common diseases that have been studied in much larger numbers of individuals and identified far greater numbers of loci. We conducted the worlds largest GWAS of AD, including studies of different ethnicities and using data imputed to the 1000 genomes reference panel. Our discovery cohort consisted of 21,483 cases and 97,977 controls from 25 studies. In addition to carrying out a fixed effects genome-wide meta-analysis of European individuals, we also included Japanese, Latin-American and African-American individuals in a trans-ethnic meta-analysis (using MANTRA). We identified 27 loci associated with AD at genome-wide significance (11 novel). Due to differences in patterns of linkage disequilibrium between ethnicities, we were able to refine the regions of interest for some previously identified loci whereas other loci showed population-specific associations. One particularly interesting association involved a series of SNPs near CD207, a gene selectively expressed in dendritic cells of the epidermis (Langerhans cells), putatively involved in antigen uptake and processing. These SNPs also showed strong association with CD207 expression in skin tissue from the MuTHER study (p=2x10-10). Thus, our results suggest a possible role for genetic factors influencing epithelial dendritic cell function in the aetiology of eczema. Our results also show a substantial genetic overlap of AD with immune-mediated diseases, particularly inflammatory bowel disease (IBD). 39 of 163 SNPs robustly associated with IBD in a recent GWAS were at least nominally associated (p<0.05) with AD in our sample (34 of these in the same direction). A gene-set enrichment analysis using MAGENTA identified 38 significantly enriched gene-sets (FDR<0.05) out of a total of >10,000 tested, and 9 additional SNPs (with p<10-5) to include in the replication phase. These gene sets predominantly belong to T cell proliferation and differentiation, cytokine and chemokine signalling, and NF-kappaB signalling pathways. 24 polymorphisms newly associated with AD are currently being tested in over 200,000 individuals in a replication phase.

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