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. Editor's summary: Several neurological disorders exhibit sex biases, and sex-determined differences in gene transcription in the brain might explain some of them. DeCasien et al. performed single-cell transcriptomic analysis of the adult human cerebral cortex across six cortical regions (see the Perspective by Tollkuhn and Breedlove). Differences between male and female brain donors varied according to cell type and region specificity, many of which were linked to known disease loci. At the cellular level, the authors did not detect any sex-biased changes in cellular proportions, suggesting that a sex difference in gene expression does not influence cell-type composition. These results are a valuable resource for understanding the mechanisms underlying sex differences in brain function and the relationship between sex and neurological disorders. —Mattia Maroso INTRODUCTION: Sex differences in brain-related health outcomes may be a consequence of differences in gene expression, which are likely to be influenced by both sex chromosome complement and circulating hormone levels. RATIONALE: Most current knowledge of molecular brain sex differences relies on studies of bulk tissue or isolated brain regions. We present a large-scale single-cell analysis of transcriptomic sex differences in the adult human brain, using 169 samples from 15 females (age 26 to 71 years) and 15 males (age 27 to 78 years) across six cortical regions, selected on the basis of in vivo neuroimaging measures of sex-biased volume. RESULT: We found that sex effects on gene expression are highly patterned across cortical regions, cell types, and genes. They are most pronounced in (i) multiple cell types in the fusiform cortex (linked to male-biased volume and sex-biased behaviors); (ii) oligodendrocytes, astrocytes, and excitatory neurons across regions; and (iii) a subset of sex chromosome and autosomal genes. More than 3000 distinct genes exhibit sex-biased expression, with 133 genes (119 autosomal) showing consistent sex differences across all region × cell type combinations. Sex chromosome genes show the largest sex differences in expression, driven by conserved X-Y gametologs, cell type–specific biases in certain X- and Y-linked genes, and escape from X-inactivation—with the list of known escapees substantially expanded through our single-cell allele-specific expression analysis. Broader effects of sex on autosomal expression are captured in 13 core signatures with varying cell type versus region specificity. These signatures are (i) shaped by regional differences in cortical metabolism and laminar architecture, (ii) enriched for diverse cellular compartments and biological processes, (iii) regulated by sex steroids and X-linked transcription factors, and (iv) linked to sex-specific genetic risk factors in sex-biased neuropsychiatric and neurodegenerative diseases. CONCLUSION: This study substantially advances the breadth, depth, and granularity of knowledge on sex differences in the human brain and provides a new open data resource to support future research. Future studies will be needed to illuminate when sex differences emerge during development and whether they are consistent across populations. Sex differences in the human brain at cell type resolution.: [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]