Self-supervised graph representation learning integrates multiple molecular networks and decodes gene-disease relationships.

Leveraging molecular networks to discover disease-relevant modules is a long-standing challenge. With the accumulation of interactomes, there is a pressing need for powerful computational approaches to handle the inevitable noise and context-specific nature of biological networks. Here, we introduce Graphene, a two-step self-supervised representation learning framework tailored to concisely integrate multiple molecular networks and adapted to gene functional analysis via downstream re-training. In practice, we first leverage GNN (graph neural network) pre-training techniques to obtain initial node embeddings followed by re-training Graphene using a graph attention architecture, achieving superior performance over competing methods for pathway gene recovery, disease gene reprioritization, and comorbidity prediction. Graphene successfully recapitulates tissue-specific gene expression across disease spectrum and demonstrates shared heritability of common mental disorders. Graphene can be updated with new interactomes or other omics features. Graphene holds promise to decipher gene function under network context and refine GWAS (genome-wide association study) hits and offers mechanistic insights via decoding diseases from genome to networks to phenotypes.