Structural and cellular transcriptome foundations of human brain disease

Genes associated with risk for brain disease exhibit characteristic expression patterns that reflect both anatomical and cell type relationships. Brain-wide transcriptomic patterns of disease risk genes provide a molecular based signature for identifying disease association, often differing from common phenotypic classification. Analysis of adult brain-wide transcriptomic patterns associated with 40 human brain diseases identified five major transcriptional patterns, represented by tumor-related, neurodegenerative, psychiatric and substance abuse, and two mixed groups of diseases. Brain disease risk genes exhibit unique anatomic transcriptomic signatures, based on differential co-expression, that often uniquely identify the disease. For cortical expressing diseases, single nucleus data in the middle temporal gyrus reveals cell type expression gradients separating neurodegenerative, psychiatric, and substance abuse diseases. By homology mapping of cell types across mouse and human, transcriptomic disease signatures are found largely conserved, but with psychiatric and substance abuse related diseases showing important specific species differences. These results describe the structural and cellular transcriptomic landscape of disease in the adult brain, highlighting significant homology with the mouse yet indicating where human data is needed to further refine our understanding of disease-associated genes.