HCNetlas: A reference database of human cell type-specific gene networks to aid disease genetic analyses.

Cell type-specific actions of disease genes add a significant layer of complexity to the genetic architecture underlying diseases, obscuring our understanding of disease mechanisms. Single-cell omics have revealed the functional roles of genes at the cellular level, identifying cell types critical for disease progression. Often, a gene impact on disease through its altered network within specific cell types, rather than mere changes in expression levels. To explore the cell type-specific roles of disease genes, we developed HCNetlas (human cell network atlas), a resource cataloging cell type-specific gene networks (CGNs) for various healthy tissue cells. We also devised 3 network analysis methods to investigate cell type-specific functions of disease genes. These methods involve comparing HCNetlas CGNs with those derived from disease-affected tissue samples. These methods find that systemic lupus erythematosus genes predominantly function in myeloid cells, and Alzheimer's disease genes mainly play roles in inhibitory and excitatory neurons. Additionally, they suggest that many lung cancer-related genes may exert their roles in immune cells. These findings suggest that HCNetlas has the potential to link disease-associated genes to cell types of action, facilitating development of cell type-resolved diagnostics and therapeutic strategies for complex human diseases.