Sex differences in the human brain: from multimodal MRI to single nucleus transcriptomics

Humans show sex-differences in numerous mental health outcomes - likely reflecting the complex interaction of biological, psychological and social factors. Mapping sex-differences in human brain organization through in vivo neuroimaging may help to unravel this complexity. However, there remains controversy regarding the extent and nature of sex-biased human brain organization from neuroimaging, and we lack information on potential cellular underpinnings of those neuroimaging sex-differences that have been reported. This talk will present new work that (1) charts reproducible structural and functional sex-differences in the human brain using multiple large-scale datasets encompassing up to ~35k individuals, and then (2) conducts single nucleus RNAseq of >1.5M cells in 180 cortical samples from 30 individuals (15 male) to resolve cell-type specific sex differences at neuroimaging hotspots of sex-biased brain anatomy. We find that humans show reproducible sex differences in regional brain volume that: exist above and beyond sex-differences in overall brain size; show a consistent spatial patterning (r~0.8) within and across samples; are small-medium in absolute effect size and orthogonal to co-occurring sex differences in brain activation; and include regions implicated in multiple psychiatric disorders. Single nucleus RNAseq at hotspots of sex-biased brain volume find similar cellular proportions in males and females (p>0.05) but extensive cell-type specific sex-differences in gene expression (FDR q<0.05) that are most prominent for glial cells and enriched for genes implicated in diverse sex-biased psychiatric conditions. This work nominates numerous anatomical and molecular brain systems that show sex-biased organization in humans – identifying potential pathways for sex-differences in psychiatric risk. These pathways represent empirically prioritized targets for sex-specific modulation of mental health outcomes.



Relevant recent publications:
- Liu, S., Seidlitz, J., Blumenthal, J. D., Clasen, L. S., & Raznahan, A. (2020). Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans. Proceedings of the National Academy of Sciences, 117(31), 18788-18798.
- DeCasien, A. R., Guma, E., Liu, S., & Raznahan, A. (2022). Sex differences in the human brain: a roadmap for more careful analysis and interpretation of a biological reality. Biology of Sex Differences, 13(1), 43.
- Shafee, R., Moraczewski, D., Liu, S., Mallard, T., Thomas, A., & Raznahan, A. (2024). A sex-stratified analysis of the genetic architecture of human brain anatomy. Nature Communications, 15(1), 8041.