A new study published on Apr. 17 examines individual brain cells from several human brain regions and finds subtle but widespread differences in gene activity between male and female brains. The findings may help explain why some psychiatric and neurological disorders affect the sexes differently, according to researchers.
The study matters because males and females, defined by XY and XX chromosomes respectively, show notable differences in risk, prevalence, and progression of many psychiatric and neurological disorders. These disparities are thought to result from both biological factors such as genetics and hormones as well as social influences. However, their consistency across cultures suggests that inherent genetic transcription differences may play a significant role.
To explore this further, Alex DeCasien and colleagues used single-nucleus RNA sequencing (snRNA-seq) to analyze tissue samples from 30 adult individuals—15 male and 15 female—across six cortical regions of the brain. Some of these regions are known for sex-based structural differences while others are not. This approach allowed for precise comparison between molecular variations related to sex.
The research found that biological sex accounted for only a small portion of overall variation in gene expression throughout the brain. Still, more than 3,000 genes showed some level of sex-biased transcription in at least one cortical region; among them were 133 genes with consistent effects across multiple brain areas and cell types. While most pronounced differences appeared on genes located on the sex chromosomes, much of the variation occurred on autosomal genes influenced mainly by sex steroid hormones.
Many genes showing these patterns overlap with those linked to neuropsychiatric or neurodegenerative conditions such as ADHD, schizophrenia, depression, or Alzheimer's disease. Jessica Tollkuhn and Marc Breedlove wrote in a related Perspective: "[DeCasien et al.] explicitly acknowledge that sex-related differences reported in their study may originate from differences in socialization and experience." They added: "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."
