A comparison of anatomic and cellular transcriptome structures across 40 human brain diseases

Area of Science:

• Neuroscience
• Genomics
• Computational Biology

Background:

• Genes linked to brain disease risk display specific expression patterns related to brain anatomy and cell types.
• Differential co-expression analysis reveals disease-specific transcriptomic signatures in the brain.

Purpose of the Study:

• To identify and analyze major transcriptomic patterns across common human brain diseases.
• To investigate cell type-specific expression gradients in the cortex for disease classification.
• To compare gene expression patterns and disease relationships between human and mouse models.

Main Methods:

• Analysis of transcriptomic patterns for 40 common human brain diseases using differential co-expression.
• Single-nucleus RNA sequencing data from the middle temporal gyrus (MTG) to examine cell type expression gradients.
• Mapping of homologous cell types between human and mouse brains.

Main Results:

• Identified 5 major transcriptional patterns associated with distinct disease groups (tumor-related, neurodegenerative, psychiatric/substance abuse, basal ganglia, hypothalamus).
• Discovered a cell type expression gradient in the human cortex (MTG) that differentiates neurodegenerative, psychiatric, and substance abuse diseases.
• Found that most disease risk genes act in homologous cell types across species, with preserved phenotypic classification despite species-specific expression.

Conclusions:

• Transcriptomic signatures provide a molecular basis for classifying and comparing brain diseases, revealing novel relationships.
• Cell type-specific expression patterns in the brain are crucial for understanding disease etiology and classification.
• Cross-species analysis highlights conserved and divergent mechanisms of disease gene action in homologous cell types.