Cellular Diversity Underpins Cortical Organization and Disease Vulnerability in the Human Brain

The cellular organization of the human brain fundamentally shapes its structure, function, and vulnerability to psychiatric disorders. However, the specific cellular contributions to laminar architecture and disease susceptibility remain elusive. Here, we estimated the distribution of molecularly defined cell types across cortical regions by integrating human single-nucleus RNA sequencing data with the Allen Human Brain Atlas microarray data. The cellular distribution profiles delineated three major cortical classes: sensory/motor, anterior association, and posterior association, each characterized by distinct cell-type enrichments. The dominant neuronal subtypes within each class exhibited specific laminar preferences that matched the variations in laminar thickness, as quantified using the BigBrain 3D histological atlas. Specifically, granular layer excitatory and parvalbumin-positive interneurons dominated sensory regions, while supragranular and infragranular neuronal subtypes enriched association cortices. Finally, by linking cell-type distributions to cortical shrinkage patterns in autism spectrum disorder, major depressive disorder, and schizophrenia, we identified cell-type-specific contributions to each disorder through predictive modeling. These findings illuminate the crucial role of cellular organization in shaping cortical structure and function, providing new insights into the cellular underpinnings of psychiatric disorders.