Journal
HUMAN MOLECULAR GENETICS
Volume 22, Issue 23, Pages 4841-4856Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt317
Keywords
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Funding
- Wellcome Trust [077326/Z/05/Z, 090066/B/09/Z, 092530/Z/10/Z, 086398/Z/08/Z]
- Medical Research Council [G0700314]
- French Ministry of Higher Education and Research
- British Skin Foundation
- Genome Quebec
- le Ministere de l'Enseignement superieur, de la Recherche, de la Science et de la Technologie (MESRST) Quebec
- McGill University
- National Eczema Society
- German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- German National Genome Research Network (NGFN-2) [NGFNPlus: 01GS0823, 01GS 0818]
- Swedish Research Council
- Stockholm County Council
- Centre for Allergy, Research, Karolinska Institutet
- Swedish Heart Lung Foundation
- DFG [WE 2678/7-1]
- Christiane Kuhne Centre for Allergy Research and Education
- Graduate School of Information Science in Health of the Technische Universitat Munchen (TUM-GSISH)
- COST action 'SkinBAD'
- National Children's Research Centre, Dublin
- Freemasons Grand Charity
- MRC [G0700314] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre] Funding Source: researchfish
- Medical Research Council [G1000758, G1000758B, G0700314] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10126] Funding Source: researchfish
- Wellcome Trust [086398/Z/08/Z] Funding Source: Wellcome Trust
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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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