A Population-scale Single-cell Spatial Transcriptomic Atlas of the Human Cortex

Abstract

The genetic and spatial determinants of cell type diversity in human cerebral cortices remain poorly defined. Here, we present a population-level single-cell spatial transcriptomic atlas of human cortices from 71 donors across the lifespan. We identified 906 layer-specific genes showing conserved and divergent laminar expression patterns between humans and other species. Spatial analysis revealed neuronal vulnerability and glial activation during aging, together with a decline in the proportion of superficial SST neurons and their interactions with other cells. Disease-associated genes exhibited high cell-type and layer-specific expression, implicating the pathogenic role of spatially specific gene expression. Spatial cis-eQTL analysis identified regulatory variants linked to genes related to diseases like Tourette syndrome. Cross-species comparison demonstrated glial expansion in the human cortex, accompanied by enhanced neuron-glia communication via the neuregulin signaling. Together, we provide a comprehensive single-cell atlas of the human cortex that is essential for understanding aging, evolution, and disease pathogenesis.