A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis

Stephan Weidinger1,2,†‡, 

Saffron A.G. Willis-Owen3,†‡, 

Yoichiro Kamatani4,†‡,

Hansjörg Baurecht1,2, 

Nilesh Morar3,5, 

Liming Liang6,7, 

Pauline Edser3, 

Teresa Street8,

Elke Rodriguez1,2, 

Grainne M O'regan9,10, 

Paula Beattie11, 

Regina Fölster-Holst12,

Andre Franke2, 

Natalija Novak13, 

Caoimhe M. Fahy14, 

Mårten C.G. Winge15,16,

Michael Kabesch20, 

Thomas Illig21,22, 

Simon Heath23, 

Cilla Söderhäll17, 

Erik Melén18,24,

Göran Pershagen18, 

Juha Kere19,25,26, 

Maria Bradley15,16, 

Agne Lieden16,

Magnus Nordenskjold16, 

John I. Harper27,28, 

W.H. Irwin Mclean29, 

Sara J. Brown29,

William O.C. Cookson3, 

G. Mark Lathrop4,23,30, 

Alan D. Irvine9,10,14 and

Miriam F. Moffatt3,*

+Author Affiliations

1. ¹Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein and
2. ²Christian-Albrechts-University of Kiel, Kiel, Germany
3. ³National Heart and Lung Institute, Imperial College, London SW3 6LY, UK
4. ⁴Fondation Jean Dausset—Centre d’Étude du Polymorphisme Humain, Paris, France
5. ⁵Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, UK
6. ⁶Department of Epidemiology and
7. ⁷Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
8. ⁸Department of Statistics, University of Oxford, Oxford OX1 3TG, UK
9. ⁹National Children's Research Centre and
10. ¹⁰Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin 12, Ireland
11. ¹¹Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK
12. ¹²Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
13. ¹³Department of Dermatology and Allergy, University of Bonn, Bonn, Germany
14. ¹⁴Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland
15. ¹⁵Dermatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
16. ¹⁶Department of Molecular Medicine and Surgery, Center for Molecular Medicine and
17. ¹⁷Department of Biosciences and Nutrition and
18. ¹⁸Institute of Environmental Medicine and
19. ¹⁹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
20. ²⁰Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Campus St. Hedwig, Germany
21. ²¹Institute of Epidemiology, Helmholtz Zentrum Munich, Munich, Germany
22. ²²Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
23. ²³CEA/Centre National de Genotypage, 91057 Evry, France
24. ²⁴Sach's Children's Hospital, Stockholm, Sweden
25. ²⁵Science for Life Laboratory, Stockholm, Sweden
26. ²⁶Research Programs Unit, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland
27. ²⁷Department of Immunobiology and Dermatology, UCL Institute of Child Health, London, UK
28. ²⁸Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK
29. ²⁹Dermatology and Genetic Medicine, College of Life Sciences, and College of Medicine, Dentistry and Nursing, University of Dundee, Dundee DD1 5EH, UK
30. ³⁰McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Canada

1. ↵*To whom correspondence should be addressed at: National Heart and Lung Institute, Imperial College London SW3 6LY, UK. Tel: +44 2075942942; Fax: +44 2073518126; Email:m.moffatt@imperial.ac.uk

• Received December 20, 2012.
• Revision received June 28, 2013.
• Accepted June 28, 2013.

 

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Abstract

Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.

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