Multitissue Integrative Analysis Identifies Susceptibility Genes for Atopic Dermatitis

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with multiple environmental and genetic factors involved in its etiology. Although lots of genetic loci associated with AD have been reported by GWASs, only a small part of phenotypic variations can be explained. To identify additional susceptibility genes on AD, we conducted a large-scale transcriptome-wide association study using a joint-tissue imputation approach in ∼840,000 European individuals combined with six precomputed gene expression weights of four AD-relevant tissues, including skin fibroblast, lymphocyte, and whole blood. The Mendelian randomization causal inference analysis was performed to estimate the causal effect of transcriptome-wide association study‒identified genes. We identified 51 genes significantly associated with AD after Bonferroni corrections, and 19 genes showed putatively causal associations such as an established gene FLG (P = 3.98 × 10^‒10) and seven genes that have not been implicated in previous transcriptome-wide association studies, such as AQP3 (P = 4.43 × 10^‒7) and PDCD1 (P = 7.66 × 10^‒7). Among them, four genes (AQP3, PDCD1, ADCY3, and DOLPP1) were further supported in differential expression analyses or the Mouse Genome Informatics database. Overall, our study identified susceptibility genes associated with AD, providing, to our knowledge, previously unreported clues in revealing the genetic mechanisms in AD.