818 Multi-condition TWAS for inflammatory skin disorders highlights roles of genetic signals in cytokine-stimulated keratinocytes

Transcriptome-wide association studies (TWAS) model the genetically regulated component (GRC) of gene expression in reference tissue to reveal potential causal genes in GWAS. Current TWAS focus on using control tissues, and studies that leverage different immune-activated tissues as references are limited. Here, we generated 400 RNA-seq samples in keratinocytes under seven different cytokine-stimulated conditions (IFNa, IFNg, IL-4, IL-13, IL-17A, IL-17A+TNF, and TNF) from 50 genotyped individuals. After modeling the GRC for 18,599 genes in each condition, we used MultiXcan to integrate the modeled transcriptome and conducted TWAS in seven common skin conditions: acne, alopecia areata (AA), atopic dermatitis (AD), psoriasis (PSO), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and vitiligo (VIT). The number of TWAS significant genes for each disease ranged from 182 to 458; notably ∼57% of these signals are contributed by at least 4 conditions. Our results illustrated that IKZF4 is significantly associated with all diseases except for PSO (p-values from 4.66×10-98 to 4.11×10-9), with the IL-13-stimulated condition contributing to the association for all diseases. Among the TWAS significant results that overlap with the GWAS signals, we were also able to highlight these potential causal genes that are also up-regulated (UR) in keratinocytes (following UR p-values are based on analyses of differentially expressed genes): LCE3D for PSO with TNF as the strongest contributing cytokine (TWAS p=1.98×10-12, UR p=2.89×10-3); RAET1L for AA with TNF (TWAS p=3.74×10-20, UR p=1.38×10-57); ITGAM for SLE with TNF (TWAS p=6.25×10-48, UR p=1.66×10-27); IL23A for VIT with IFNa (TWAS p=9.97×10-35, UR p=2.54×10-89). This study reveals the causal gene candidates that exhibit cytokine-dependent regulation for common complex skin conditions, highlighting the roles of specific susceptibility regions in keratinocytes.