Single-cell transcriptomic mendelian randomization and co-localization reveal immune-mediated regulatory mechanisms...

Atopic dermatitis (AD) is a chronic inflammatory skin condition with increasing prevalence; however, the underlying immune mechanisms remain poorly understood. Precision therapeutics have shown promise, yet significant unmet clinical needs remain. Single-cell expression quantitative trait loci (sc-eQTL) combined with genome-wide association studies (GWAS) and mendelian randomization (MR) can provide cell-type-specific causal evidence for immune mechanisms in complex diseases METHODS: We integrated sc-eQTL data from 14 immune cell types (OneK1K cohort, n = 982) with AD GWAS summary statistics from FinnGen (n = 31,245) and GWAS Catalog (n = 22,474). We performed two-sample MR using inverse variance weighting and Wald ratio methods, with MR-Egger, MR-PRESSO, and Steiger directionality tests ensuring robustness. Co-localization analysis confirmed shared causal variants, and functional enrichment analyses explored candidate gene mechanisms.

We identified 14 immune cell-specific hub genes (CD52, CD4 NC, IL2RA, TNF, HLA-DQB2, and others) with strong co-localization evidence (PP·H4 > 0.7). Enrichment analysis revealed significant clustering in MHC class II protein complexes and (e.g., HLA-DR, HLA-DP, HLA-DQ) and partially in TNF and MHC-I classes like HLAC. Pathway analysis indicated significant enrichment in immune-related pathways, including asthma and inflammatory bowel disease. Additionally, 46 drugs targeting these genes were identified, with 13 causal genes overlapping with known druggable targets, such as alemtuzumab (CD52), daclizumab (IL2RA), and TNF inhibitors.

Our study provides genetic evidence supporting a causal role for immune cell-specific genes in AD susceptibility. The 14 hub genes and associated druggable targets establish a foundation for precision immunotherapy development in AD.