Structural and cellular transcriptome foundations of human brain disease

The intersection of human genetics and brain transcriptomics promises to reveal the structural and cellular locus of brain diseases via selective co-expression of risk genes. We find that adult brain-wide transcriptomic profiles of 40 human brain diseases identify four major transcriptional patterns, represented by tumor-related, neurodegenerative, psychiatric and substance abuse, and a mixed group of diseases, with some unexpected disease associations. Based on differential co-expression using bulk transcriptomics, the majority of brain diseases exhibit unique regional transcriptomic signatures that strongly reflect neuronal versus non-neuronal divisions and variation in excitatory and inhibitory neurons across the brain. Single cell transcriptomic data confirms and refines the relationship of different diseases to specific neuronal and non-neuronal subclasses. Disease signatures are largely conserved between mouse and human at the higher cell class level, but with significant species differences emerging at the finer subclass level that may help explain human-specific disease susceptibility.