Single-Cell Analysis of Sex and Gender Differences in the Human Brain During Development and Disease

Sex and gender (SG) differences in the human brain are of interest to society and science as numerous processes are impacted by them, including brain development, behavior, and diseases. By collecting publicly available single-cell data from the in-utero to elderly age in healthy, Alzheimer's disease and multiple sclerosis samples, we identified and characterized SG-biased genes in ten brain cell types across 9 age and disease groups. Sex and gender differences in the transcriptome were present throughout the lifespan and across all cell types. Although there was limited overlap among SG-biased genes across different age and disease groups, we observed significant functional overlap. Female-biased genes are consistently enriched for brain-related processes, while male-biased genes are enriched for metabolic pathways. Additionally, mitochondrial genes showed a consistent female bias across cell types. We also found that androgen response elements (not estrogen) were significantly enriched in both male- and female-biased genes, and thymosin hormone targets being consistently enriched only in male-biased genes. We systematically characterised SG differences in brain development and brain-related disorders at a single-cell level, by analysing a total of publicly available 419,885 single nuclei from 161 human brain samples (72 females, 89 males). The significant enrichment of androgen (not estrogen) response elements in both male- and female-biased genes suggests that androgens are important regulators likely establishing these SG differences. Finally, we provide full characterization of SG-biased genes at different thresholds for the scientific community as a web resource.