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 w840,000 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 infer-ence 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 x 10-10) and seven genes that have not been implicated in previous transcriptome-wide association studies, such as AQP3 (P = 4.43 x 10-7) and PDCD1 (P = 7.66 x 10-7). Among them, four genes (AQP3, PDCD1, ADCY3, and DOLPP1) were further supported in dif-ferential expression analyses or the Mouse Genome Informatics database. Overall, our study identified suscep-tibility genes associated with AD, providing, to our knowledge, previously unreported clues in revealing the mechanisms in AD.