High-resolution study maps molecular differences across six human cortical regions

A new analysis of individual brain cells across several human brain regions reveals subtle but widespread differences in gene activity between male and female brains. This may help explain why some psychiatric and neurological disorders appear to affect the biological sexes differently, researchers report.

Males and females, as defined by individuals with an XY and XX chromosomes, respectively, show marked differences in risk, prevalence, and progression of many psychiatric and neurological disorders. While these disparities likely arise from the interplay of biological and social influences, their consistency across cultures and predictable timing over development suggest that sex-determined differences in gene transcription in the brain may play an important role.

To investigate this possibility, Alex DeCasien and colleagues conducted a high-resolution analysis of gene expression in the human brain using single-nucleus RNA sequencing (snRNA-seq) on tissue samples from 30 adult individuals (15 male and 15 female). They specifically focused on six cortical regions – some known to exhibit sex differences in brain structure and others not known to – allowing the authors to more precisely compare between molecular and anatomical variation.

DeCasien et al. found that biological sex explained only a very small fraction of variation in gene expression across the brain. Nevertheless, the analysis revealed more than 3,000 genes that exhibited some degree of sex-biased transcription in at least one cortical region, and 133 with consistent effects across brain regions and cell types. While the strongest differences were found in genes located on the sex chromosomes, most sex-related variation occurred in autosomal genes not linked to sex chromosomes and driven predominantly by sex steroid hormones.

Notably, many of these genes showing sex-biased expression overlap with genetic variants associated with neuropsychiatric and neurodegenerative disorders, including ADHD, schizophrenia, depression, and Alzheimer's disease. "[DeCasien et al.] explicitly acknowledge that sex-related differences reported in their study may originate from differences in socialization and experience," write Jessica Tollkuhn and Marc Breedlove in a related Perspective. "A role for such social influences could be ruled out if sex differences in gene expression are present before birth, and future studies could address this question."