Learning Multi-Relational Graph Representations for DNA Methylation-Based Biological Age Estimation

TL;DR

This paper introduces RelAge-GNN, a multi-relational graph neural network that models complex relationships among CpG sites to improve biological age prediction from DNA methylation data.

Contribution

It constructs and integrates three types of graphs capturing biological relationships among CpG sites, enhancing age prediction accuracy and interpretability.

Findings

RelAge-GNN outperforms state-of-the-art methods in accuracy and correlation with chronological age.

The model improves sensitivity in detecting age acceleration in disease cohorts.

Post hoc analysis reveals biologically meaningful contributions of relational structures and CpG sites.

Abstract

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/.