282 A genome-wide association study of 4.6 million individuals in the EAGLE eczema consortium identifies 100 loci associated with atopic dermatitis

We have undertaken a large-scale genome-wide association study of atopic dermatitis. In our discovery analysis (865,244 individuals of European ancestry and 127,663 non-Europeans) genetic data was imputed to the HRC reference and variants >1% minor allele frequency were meta-analysed. 81 loci (32 novel) were associated (p<5x10-8) in Europeans, including loci that implicate SATB1, NEU4/PDCD1, TNFRSF1B and RGS14/LMAN2 genes. 19 additional loci (14 novel) were identified in a multi-ancestry analysis. Replication was sought in 2.9 million Europeans, 525,348 Latino and 174,015 African ancestry individuals. All 81 European loci replicated. 11 multi-ancestry loci replicated in at least one of European, Latino or African ancestry replication datasets. CD3 primary blood cells showed the strongest enrichment of GWAS signals amongst DNase I hypersensitive peaks (OR=5.8, p=2x10-13) in a GARFIELD analysis, whereas the strongest enrichment in skin was found in foreskin keratinocytes (OR=2.0, p=0.008). In the eQTL enrichment with GTEx data (in MAGMA) the strongest enrichment was observed in whole blood (p=2x10-14), with other tissues (including skin, p=9x10-6) showing weaker, but significant enrichment. LD score regression found high levels of genetic correlation between atopic dermatitis and expected traits: asthma (rg=0.53), hay fever (rg=0.51) and eosinophil count (rg=0.27), but also interesting genetic correlations with depression and anxiety (rg=0.17) and gastritis (rg=0.31). Multi-omic data sources (eQTL, pQTL, differential expression, Mendelian gene and variant effect prediction annotations) were combined in our gene prioritisation pipeline to identify potential causal genes at the 81 European loci. Many of these genes are in pathways previously implicated in atopic dermatitis (e.g. cytokine signalling, antigen presentation and NF-κB inflammatory signalling).