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Multi-cytokine based TWAS for seven inflammatory skin disorders identify candidate causal genes in keratinocytes.

The Journal of allergy and clinical immunology

Authors: Haihan Zhang, Matthew T Patrick, Mrinal K Sarkar, Rachael Bogle, Qinmengge Li, Ranjitha Uppala, Bethany E Perez White, Lynn Petukhova, Nick Dand, Philip E Stuart, Angela M Christiano, Michael A Simpson, Jonathan N Barker, Stephan Weidinger, Robert L Modlin, Regina C Betz, Dinesh Khanna, John Varga, J Michelle Kahlenberg, Kevin He, James T Elder, Xiang Zhou, Johann E Gudjonsson, Lam C Tsoi

BACKGROUND: Transcriptome-wide association studies (TWAS) identify genetically regulated expression (GReX) components and can pinpoint causal genes in GWAS, but are often limited by using a single cellular context.

OBJECTIVE: We hypothesized that modeling GReX across multiple conditions could enhance power to identify causal genes for complex inflammatory diseases.

METHODS: We conducted TWAS on 400 transcriptomes under eight pro-inflammatory cytokine stimulations in keratinocytes, modeling GReX for 18,599 genes against GWAS from seven inflammatory skin diseases: atopic dermatitis, psoriasis, acne, alopecia areata, systemic sclerosis, SLE, and vitiligo.

RESULTS: Our TWAS identified 274 loci from the seven diseases that harbor a single significant TWAS gene association. We nominated causal genes and their associated pro-inflammatory cytokine stimuli, including ERAP2 for psoriasis with IL-17A+TNF stimulation; WNT10A for acne with IFNγ stimulation; RAET1L, MAP3K11, and ITGAM for alopecia areata, acne, and SLE, respectively, with TNF stimulation. Notably, our TWAS-identified genes showed overwhelming evidence of colocalization with GWAS signals (p = 1.03×10), and our method successfully captured over 85% of all genes with colocalizing eQTLs. Using single cell resolution spatial profiling, we further demonstrated the modulation of TWAS signals in keratinocytes by close proximity to TNF/IL-17 expressing cells in psoriatic skin.

CONCLUSION: Modeling gene expression across relevant cellular states substantially improves the power and resolution of TWAS.

CLINICAL IMPLICATION: Our findings indicate that genetic signals for complex skin conditions shape inflammatory responses in the epithelium and provide a roadmap of how susceptibility loci modulate shared and unique cytokine responses in keratinocytes for different inflammatory skin diseases.

Copyright © 2026. Published by Elsevier Inc.

PMID: 42203178

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