arXiv:2603.02273cs.LG2026-03

用多模态图注意力模型找阿尔茨海默病关键致病基因,比传统方法更准。

Graph Attention Based Prioritization of Disease Responsible Genes from Multimodal Alzheimer's Network

  • 用Transformer学习基因嵌入,结合多组学数据做注意力评分
  • 在阿尔茨海默病通路中富集得分达3.9,显著优于传统方法
  • 能发现新致病基因和跨疾病共表达模块,适合神经退行性疾病研究

识别疾病相关基因是理解阿尔茨海默病(AD)等复杂疾病分子机制的核心。传统网络方法依赖静态中心性指标,难以捕捉跨模态生物异质性。本文提出NETRA(基于Transformer表示与注意力的节点评估)框架,用注意力驱动的评分替代启发式中心性度量。以阿尔茨海默病为例,分别基于微阵列、单细胞和单核RNA测序数据构建基因调控网络。利用随机游走序列训练BERT模型获取全局基因嵌入,同时用变分自编码器压缩各模态基因表达特征。这些表示与蛋白质-蛋白质相互作用、基因本体语义相似性及基于扩散的基因相似性等辅助网络整合成统一多模态图。图变压器生成NETRA分数,实现疾病特异且上下文感知的基因相关性量化。基因集富集分析显示,NETRA在阿尔茨海默病通路中的标准化富集得分为约3.9,显著优于经典中心性度量和扩散模型。排名靠前的基因富集于多个神经退行性通路,恢复了已知的晚发性阿尔茨海默病易感位点chr12q13,揭示保守的跨疾病基因模块。该框架保持了生物学上真实的重尾网络拓扑结构,可轻松扩展至其他复杂疾病。

原文摘要 · Abstract (English)

Prioritizing disease-associated genes is central to understanding the molecular mechanisms of complex disorders such as Alzheimer's disease (AD). Traditional network-based approaches rely on static centrality measures and often fail to capture cross-modal biological heterogeneity. We propose NETRA (Node Evaluation through Transformer-based Representation and Attention), a multimodal graph transformer framework that replaces heuristic centrality metrics with attention-driven relevance scoring. Using AD as a case study, gene regulatory networks are independently constructed from microarray, single-cell RNA-seq, and single-nucleus RNA-seq data. Random-walk sequences derived from these networks are used to train a BERT-based model for learning global gene embeddings, while modality-specific gene expression profiles are compressed using variational autoencoders. These representations are integrated with auxiliary biological networks, including protein-protein interactions, Gene Ontology semantic similarity, and diffusion-based gene similarity, into a unified multimodal graph. A graph transformer assigns NETRA scores that quantify gene relevance in a disease-specific and context-aware manner. Gene set enrichment analysis shows that NETRA achieves a normalized enrichment score of about 3.9 for the Alzheimer's disease pathway, substantially outperforming classical centrality measures and diffusion models. Top-ranked genes enrich multiple neurodegenerative pathways, recover a known late-onset AD susceptibility locus at chr12q13, and reveal conserved cross-disease gene modules. The framework preserves biologically realistic heavy-tailed network topology and is readily extensible to other complex disorders.

基因优先级多模态图神经网络阿尔茨海默病

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