The Journal of allergy and clinical immunology · 2026
Multicytokine-based transcriptome-wide association study for 7 inflammatory skin disorders identifies candidate causal genes in keratinocytes.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Zhang Haihan, Patrick Matthew T, Sarkar Mrinal K, Bogle Rachael, Li Qinmengge, Uppala Ranjitha, Perez White Bethany E, Petukhova Lynn, Dand Nick, Stuart Philip E, Christiano Angela M, Simpson Michael A, Barker Jonathan N, Weidinger Stephan, Modlin Robert L, Betz Regina C, Khanna Dinesh, Varga John, Kahlenberg J Michelle, He Kevin, Elder James T, Zhou Xiang, Gudjonsson Johann E, Tsoi Lam C
Аннотация
BACKGROUND: Transcriptome-wide association studies (TWAS) identify genetically regulated expression (GReX) components and can pinpoint causal genes in genome-wide association studies but are often limited by a single-cell 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 8 proinflammatory cytokine stimulations in keratinocytes, modeling GReX for 18,599 genes against genome-wide association studies from 7 inflammatory skin diseases: atopic dermatitis, psoriasis, acne, alopecia areata, systemic sclerosis, systemic lupus erythematosus, and vitiligo.
RESULTS: Our TWAS identified 274 loci from the 7 diseases that harbor a single significant TWAS gene association. We nominated causal genes and their associated proinflammatory cytokine stimuli, including ERAP2 for psoriasis with IL-17A + TNF-α stimulation; WNT10A for acne with IFN-γ stimulation; and RAET1L, MAP3K11, and ITGAM for alopecia areata, acne, and systemic lupus erythematosus, respectively, with TNF stimulation. Notably, our TWAS-identified genes showed overwhelming evidence of colocalization with genome-wide association study signals (P = 1.03 × 10-15), and our method successfully captured >85% of all genes with colocalizing expression quantitative trait loci. Single-cell-resolution spatial profiling 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.
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 8 proinflammatory cytokine stimulations in keratinocytes, modeling GReX for 18,599 genes against genome-wide association studies from 7 inflammatory skin diseases: atopic dermatitis, psoriasis, acne, alopecia areata, systemic sclerosis, systemic lupus erythematosus, and vitiligo.
RESULTS: Our TWAS identified 274 loci from the 7 diseases that harbor a single significant TWAS gene association. We nominated causal genes and their associated proinflammatory cytokine stimuli, including ERAP2 for psoriasis with IL-17A + TNF-α stimulation; WNT10A for acne with IFN-γ stimulation; and RAET1L, MAP3K11, and ITGAM for alopecia areata, acne, and systemic lupus erythematosus, respectively, with TNF stimulation. Notably, our TWAS-identified genes showed overwhelming evidence of colocalization with genome-wide association study signals (P = 1.03 × 10-15), and our method successfully captured >85% of all genes with colocalizing expression quantitative trait loci. Single-cell-resolution spatial profiling 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.