High dimensional co-expression networks enable discovery of transcriptomic drivers in complex biological systems

Biological systems are immensely complex, organized into a multi-scale hierarchy of functional units based on tightly-regulated interactions between distinct molecules, cells, organs, and organisms. While experimental methods enable transcriptome-wide measurements across millions of cells, the most ubiquitous bioinformatic tools do not support systems-level analysis. Here we present hdWGCNA, a comprehensive framework for analyzing co-expression networks in high dimensional transcriptomics data such as single-cell and spatial RNA-seq. hdWGCNA provides built-in functions for network inference, gene module identification, functional gene enrichment analysis, statistical tests for network reproducibility, and data visualization. In addition to conventional single-cell RNA-seq, hdWGCNA is capable of performing isoform-level network analysis using long-read single-cell data. We showcase hdWGCNA using publicly available single-cell datasets from Autism spectrum disorder and Alzheimers disease brain samples, identifying disease-relevant co-expression network modules in specific cell populations. hdWGCNA is directly compatible with Seurat, a widely-used R package for single-cell and spatial transcriptomics analysis, and we demonstrate the scalability of hdWGCNA by analyzing a dataset containing nearly one million cells.