Abstract: Here, we performed a comprehensive intra-tissue and inter-tissue multilayer network analysis of the human transcriptome. We generated an atlas of communities in gene co-expression networks in 49 tissues (GTEx v8), evaluated their tissue specificity, and investigated their methodological implications. UMAP embeddings of gene expression from the communities (representing nearly 18% of all genes) robustly identified biologically-meaningful clusters. Notably, new gene expression data can be embedded into our algorithmically derived models to accelerate discoveries in high-dimensional molecular datasets and downstream diagnostic or prognostic applications. We demonstrate the generalisability of our approach through systematic testing in external genomic and transcriptomic datasets. Methodologically, prioritisation of the communities in a transcriptome-wide association study of the biomarker C-reactive protein (CRP) in 361,194 individuals in the UK Biobank identified genetically-determined expression changes associated with CRP and led to considerably improved performance. Furthermore, a deep learning framework applied to the communities in nearly 11,000 tumors profiled by The Cancer Genome Atlas across 33 different cancer types learned biologically-meaningful latent spaces, representing metastasis (p < 2.2 × 10−16) and stemness (p < 2.2 × 10−16). Our study provides a rich genomic resource to catalyse research into inter-tissue regulatory mechanisms, and their downstream consequences on human disease.