Genome-Wide Integration of Genetic and Genomic Studies of Atopic Dermatitis: Insights into Genetic Architecture and Pathogenesis

Atopic dermatitis (AD) is a common heterogeneous, chronic, itching, and inflammatory skin disease. Genetic studies have identified multiple AD susceptibility genes. However, the genetic architecture of AD has not been elucidated. In this study, we conducted a large-scale meta-analysis of AD (35,647 cases and 1,013,885 controls) to characterize the genetic basis of AD. The heritability of AD in different datasets varied from 0.6 to 7.1%. We identified 31 previously unreported genes by integrating multiomics data. Among the 31 genes, MCL1 was identified as a potential treatment target for AD by mediating gene‒drug interactions. Tissue enrichment analyses and phenome-wide association study provided strong support for the role of the hemic and immune systems in AD. Across 1,207 complex traits and diseases, genetic correlations indicated that AD shared links with multiple respiratory phenotypes. The phenome-wide Mendelian randomization analysis (Mendelian randomization‒phenome-wide association study) revealed that the age of onset of diabetes exhibited a positive causal effect on AD (inverse-variance weighted β = 0.39, SEM = 0.09, P = 2.77 × 10-5). Overall, these results provide important insights into the genetic architecture of AD and will lead to a more thorough and complete understanding of the molecular mechanisms underlying AD.