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Pathway-level epigenetic modeling illuminates the methylation architecture to asthma risk across tissues
Zhongting Huang1, Yuxin Liu1, Fuqiang Cai2
1Center for Intelligent Medicine, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, No. 6, 2nd Nanjiang Road, Nansha District, Guangzhou, 511462, China.
Epigenetics & Chromatin
|June 19, 2026
Summary
This study reveals pathway-level DNA methylation patterns linked to asthma, highlighting roles of metabolism and development. These findings offer insights into asthma
Area of Science:
- Epigenetics
- Systems Biology
- Respiratory Medicine
Background:
- Asthma is a complex airway disease with unclear mechanisms.
- Genetic factors alone do not fully explain asthma's heterogeneity.
- DNA methylation bridges genetics and environment but requires better interpretability.
Purpose of the Study:
- To develop a pathway-level epigenetic framework for asthma.
- To identify biologically interpretable methylation mechanisms in asthma.
- To assess the framework's cross-tissue and cross-cohort performance.
Main Methods:
- Developed a multi-cohort, interpretable epigenetic framework.
- Utilized a linear support vector classifier with pathway-derived methylation scores.
- Applied SHapley Additive exPlanations (SHAP) for pathway contribution analysis and FDR correction.
Main Results:
- Achieved high AUC values (0.736-0.980) across airway and blood samples.
- Identified key pathways: amino acid metabolism, developmental programs, metabolic-immune transport, and neuroimmune signaling.
- Demonstrated direct and indirect pathway influences on asthma via eosinophils, epithelial dynamics, and inflammation.
Conclusions:
- A pathway-level methylation model provides biological interpretability for asthma.
- The model associates with asthma severity and molecular heterogeneity.
- Findings support understanding epigenetic, immune, and metabolic signatures for precision medicine.
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