Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans

Humans display reproducible sex differences in cognition and behavior, which may partly reflect intrinsic sex differences in regional brain organization. However, the consistency, causes and consequences of sex differences in the human brain are poorly characterized and hotly debated. In contrast, recent studies in mice-a major model organism for studying neurobiological sex differences-have established: 1) highly consistent sex biases in regional gray matter volume (GMV) involving the cortex and classical subcortical foci, 2) a preponderance of regional GMV sex differences in brain circuits for social and reproductive behavior, and 3) a spatial coupling between regional GMV sex biases and brain expression of sex chromosome genes in adulthood. Here, we directly test translatability of rodent findings to humans. First, using two independent structural-neuroimaging datasets (n > 2,000), we find that the spatial map of sex-biased GMV in humans is highly reproducible (r > 0.8 within and across cohorts). Relative GMV is female biased in prefrontal and superior parietal cortices, and male biased in ventral occipitotemporal, and distributed subcortical regions. Second, through systematic comparison with functional neuroimaging meta-analyses, we establish a statistically significant concentration of human GMV sex differences within brain regions that subserve face processing. Finally, by imaging-transcriptomic analyses, we show that GMV sex differences in human adulthood are specifically and significantly coupled to regional expression of sex-chromosome (vs. autosomal) genes and enriched for distinct cell-type signatures. These findings establish conserved aspects of sex-biased brain development in humans and mice, and shed light on the consistency, candidate causes, and potential functional corollaries of sex-biased brain anatomy in humans.