Background: Incorporation of gene expression when estimating polygenic risk scores (PRS) in atopic dermatitis (AD) may provide additional insights in disease pathogenesis and enhance predictive accuracy. Objective: In this study, we developed polygenic transcriptome risk scores (PTRSs) derived from AD-enriched tissues and evaluated their performance against traditional PRS models and a baseline risk model incorporating eosinophil and lymphocyte counts in the prediction of AD. Methods: We conducted transcriptome-wide association studies (TWAS) using the PrediXcan framework to construct tissue-specific PTRSs. Risk score performance was assessed in 256888 Europeans (10,816 cases) and validated in an independent cohort of 64152 Europeans (2669 cases) from the UK Biobank. Results: We observed a modest correlation between PRS and PTRS, exerting independent effects on AD risk. While PRS demonstrated superior predictive performance compared to single-tissue PTRSs, combining both models significantly enhanced prediction accuracy, yielding a c-statistic of 0.646 (95% confidence intervals: 0.634– 0.656). Notably, tissue-specific PTRSs revealed stronger associations with baseline risk factors, where Eppstein-Bar virus (EBV)-transformed lymphocytes and unexposed skin PTRSs tissues reported positive associations with lymphocyte counts. Conclusion: Our findings highlight the value of integrating transcriptome-based risk models to incorporating additional omics layer to refine risk prediction and enhance our understanding of genetic architecture of complex traits.

The authors have declared no competing interest.

This investigation was supported in part by a research grant from the National Eczema Association NEA23-CRG186. A.B.-A. and L.P. were funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 821511 (BIOMAP). The J.U. receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author's view and the J.U. is not responsible for any use that may be made of the information it contains. A.B.A. and L.P. and work in a research unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4).

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