Susceptibility Genes Associated With Atopic Dermatitis Identified

The study found 19 potential causal genes tied to AD, including 7 genes that had not previously been implicated.

Susceptibility genes associated with atopic dermatitis (AD) have been identified, according to study findings published in the Journal of Investigative Dermatology.

Genome-wide association studies (GWASs) have reported significant numbers of genetic loci associated with atopic dermatitis. Researchers in China sought to identify additional susceptibility genes tied to atopic dermatitis.

They conducted a transcriptome-wide association study (TWAS) that included approximately 840,000 European individuals and using a joint-tissue imputation approach linked with 6 precomputed gene expression weights of 4 atopic dermatitis-relevant tissues. Relevant tissues included whole blood, lymphocyte, and skin fibroblast. To estimate the causal effect of TWAS-identified genes, they performed a Mendelian randomization causal inference analysis.

Following Bonferroni corrections, researchers reported identifying 51 genes significantly associated with atopic dermatitis. Researchers observed that half these genes showed significant associations in only a specific tissue — dermatitis-associated gene PDCD1 only identified in the not sun-exposed skin (P-value =7.66×10-7) and IL6R only identified in whole blood (P =4.55×10-7). They noted 1 gene, PDLIM4, showed associations that were significant in all tissues: sun-exposed skin (P =1.71×10-9), not sun-exposed skin (P =2.91×10-8), GEUVADIS LCLs (P =3.94×10-11), EBV-transformed lymphocytes (P =1.54×10-8), whole blood (P =1.92×10-8), and fibroblasts (P =1.19×10-8).

Our findings further delineate the biological interpretations on atopic dermatitis and will provide novel insights for revealing the genetic mechanisms in the regulation of atopic dermatitis.

They found that 19 genes revealed putatively causal associations (significant in causal effect inference analysis), and they found 7 genes not linked in previously conducted GWASs, including AQP3 in the sun exposed skin (P =4.43×10-7) and PDCD1 in the not sun-exposed skin (P =7.66×10-7). Among these 7 genes, researchers noted that AQP3, PDCD1, ADCY3, and DOLPP1 were further supported in Mouse Genome Informatics databases or in differential expression analyses.

They noted positive correlations across skin-relevant tissues for the expression correlations of all putatively causal genes. They found negative correlations in a part of the gene expression in the EBV-transformed lymphocytes and whole blood, compared with other tissues.

Study limitations include that all study individuals were of European ancestry and results may not be generalizable for other ethnicities with varying genetic backgrounds, not every gene was chosen for TWAS calculation so potential relevant genes may be lost, genes in the major histocompatibility complex region excluded, difficulty eliminating the effect of co-regulation and distinguish true causal genes, and some important genes associated with atopic dermatitis may have been neglected.

Researchers concluded, “Our study identified susceptibility genes associated with atopic dermatitis, providing new clues in revealing the genetic mechanisms in atopic dermatitis.” Researchers went on to state “Our findings further delineate the biological interpretations on atopic dermatitis and will provide novel insights for revealing the genetic mechanisms in the regulation of atopic dermatitis.”

References:

Wu H, Ke X, Huang W, et al. Multi-tissue integrative analysis identifies susceptibility genes for atopic dermatitis. J Invest Dermatol. Published online September 22, 2022. doi:10.1016/j.jid.2022.09.006