用图神经网络融合多种基因关联,提升甲基化测龄精度与疾病敏感性。
Learning Multi-Relational Graph Representations for DNA Methylation-Based Biological Age Estimation

- 构建三种基因关系图,联合学习甲基化位点间的复杂关联。
- 在大规模数据上准确预测生物年龄,相关性优于现有方法。
- 可解释性强,揭示关键位点与关系,适合衰老与疾病研究。
衰老时钟旨在通过可观测生物标志物估算生物年龄,即生理状态与日历年龄的差异,广泛用于健康评估和疾病分析。DNA甲基化因其稳定性及与衰老强相关性,成为重要标志物,近年基于学习的方法已显著提升预测性能。然而,现有方法多将CpG位点视为独立特征,忽视其复杂的生物学关系。本文提出RelAge-GNN,一种多关系图神经网络框架,用于基于甲基化的年龄预测。该方法构建三种互补图:共甲基化模式、基因组共定位关系、基因水平关联,并由独立的GNN分支建模,再通过可学习门控机制自适应融合表示。在大规模数据集上的实验表明,RelAge-GNN达到有竞争力的准确性,且与日历年龄的相关性高于当前最优方法。此外,模型在不同疾病队列中对年龄加速的检测敏感性更强,凸显其在疾病表征中的潜力。通过事后可解释性分析,量化了不同关系结构和CpG位点的贡献,提供生物学意义明确的洞见,为衰老相关研究指明方向。代码已公开于:https://anonymous.4open.science/r/RelAge-GNN-F1E3/。
原文摘要 · Abstract (English)
Aging clocks aim to estimate biological age, a measure of physiological state distinct from chronological age, from observable biomarkers, and are widely used for health assessment and disease analysis. DNA methylation is a particularly informative biomarker due to its stability and strong association with aging, and recent learning-based approaches have improved predictive performance. However, most existing methods treat CpG sites as independent features, overlooking the complex and heterogeneous biological relationships among them. We propose RelAge-GNN, a multi-relational graph neural network framework for DNA methylation-based age prediction. Our method constructs three complementary graphs capturing co-methylation patterns, genomic co-localization, and gene-level associations among CpG sites. Each graph is modeled by an independent GNN branch, and a learnable gating mechanism adaptively fuses the resulting representations. Experiments on large-scale datasets show that RelAge-GNN achieves competitive accuracy and stronger correlation with chronological age compared to state-of-the-art methods. Moreover, the model exhibits improved sensitivity in detecting age acceleration across diverse disease cohorts, highlighting its potential utility for disease characterization. Finally, through post hoc interpretability analyses, we quantify the contributions of different relational structures and CpG sites, providing biologically meaningful insights and suggesting potential directions for aging-related research. Our code is available at: https://anonymous.4open.science/r/RelAge-GNN-F1E3/.
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