Cell type characterization of spatiotemporal gene co-expression modules in Down syndrome brain

Down syndrome (DS) is the most common genetic cause of intellectual disability and increases the risk of other brain-related dysfunctions, like seizures, early-onset Alzheimer's disease, and autism. To reveal the molecular profiles of DS-associated brain phenotypes, we performed a meta-data analysis of the developmental DS brain transcriptome at cell type and co-expression module levels. In the DS brain, astrocyte-, microglia-, and endothelial cell-associated genes show upregulated patterns, whereas neuron-and oligodendrocyte-associated genes show downregulated patterns. Weighted gene co-expression network analysis identified cell type-enriched co-expressed gene modules. We present eight representative cell-type modules for neurons, astrocytes, oligodendrocytes, and microglia. We classified the neuron modules into glutamatergic and GABAergic neurons and associated them with detailed subtypes. Cell type mod-ules were interpreted by analyzing spatiotemporal expression patterns, functional annotations, and co-expression networks of the modules. This study pro-vides insight into the mechanisms underlying brain abnormalities in DS and related disorders.

Automated summary

Down syndrome (DS) is the most common genetic cause of intellectual disability and is associated with an increased risk of brain-related dysfunctions. A meta-data analysis of the DS brain transcriptome revealed upregulated genes in astrocytes, microglia, and endothelial cells, while downregulated genes were observed in neurons and oligodendrocytes. Cell type-enriched co-expressed gene modules were identified, including representatives from neurons, astrocytes, oligodendrocytes, and microglia. This study provides insights into the mechanisms underlying brain abnormalities in DS and related disorders.