Sex effects on gene expression across the human cerebral cortex at cell type resolution

Sex differences in neurodevelopmental, psychiatric, and neurodegenerative disease susceptibility may arise from sex chromosome and hormonal influences on cell type-specific gene expression. We present a single-cell transcriptomic analysis of adult human cortex performed using 169 samples from 15 females and 15 males (age 26 to 78 years) across six regions selected according to their sex-biased volumes. Sex-based analysis identified the strongest differences in the fusiform cortex, glia, and excitatory neurons and among sex-chromosome genes. More than 3000 genes showed sex-biased expression, including 133 with consistent effects across regions and cell types. Core autosomal signatures linked sex differences to cortical architecture, hormone-responsive regulation, and genetic risk for sex-biased brain disorders. This study advances our understanding of sex differences in human brains and provides a valuable resource to support future research.