Study Offers a “Treasure Trove” of Clues to Sex Differences in the Brain

Brain conditions affect men and women differently. Men have higher rates of attention-deficit/hyperactivity disorder, while mood disorders appear to be more common in women. Are these statistics quirks of our health systems, or do they have a biological origin? Previous studies have tried to answer whether biological sex alters the brain at a genetic level by analyzing bulk brain tissue samples, which obscure cellular level processes.

A new study, led by Alex DeCasien, a neurogeneticist at the National Institute on Aging, offers a clearer view by analyzing gene expression in 169 brain samples from 15 men and 15 women at single-cell resolution.¹ The researchers found a link between sex and changes in the expression of more than 3000 genes across multiple brain regions, which may shape disease risk. It’s currently unclear whether the differences are caused by genetics or by different socialization between genders, but the results provide a “treasure trove” of information, experts say.

Small But Consistent Variation

DeCasien and her team used single-nucleus RNA sequencing to analyze six cortical regions from donors aged 26-78. Previous analyses of sex differences in the brain have shown that certain brain regions have larger gray matter volume in men or women.² DeCasien’s team looked at an equal number of regions that are larger in women, larger in men, or show no differences.

The team found that the difference in volume wasn’t due to variations in cell numbers. Instead, they think that differences in neuron size and shape may be responsible.

When they examined gene expression levels in detail, they found that sex accounted for less than 1% of the variation in expression across genes. Still, more than 3000 genes showed sex variation in one or more cortical regions.

The largest differences, unsurprisingly, occurred in genes located on the X and Y sex chromosomes. But most of the genes that varied were not located on sex chromosomes – a surprise, given that scientists have previously identified few autosomal genes with sex-linked variation in the brain.

Most of these differences, the authors noted, seem to be linked to sex hormone expression. Promoters of genes expressed more in women contained elements that responded to the female sex hormones estrogen and progesterone, and those expressed more in men were enriched for elements that responded to testosterone.

Links to Brain Conditions

What do these differences mean in practice? DeCasien’s team looked at the functions of the sex-biased genes. The genes were linked to hormone signaling pathways, extracellular matrix components, metabolic processes, and synaptic functions.

Sex-biased genes also overlapped with locations in the genome linked to brain disorders, including ADHD, schizophrenia, and Alzheimer’s disease. Detailed future work will need to investigate these links individually, the authors noted.

In a separate commentary, Cold Spring Harbor Laboratory neuroscientist Jessica Tollkuhn and Stephen Marc Breedlove, a neuroscientist at Michigan State University, said the findings “provide a treasure trove for the discovery of biomarkers of and/or therapeutic targets for differential disease risk in men and women.”³ Tollkuhn and Breedlove were not involved in the current study.

Despite the evidence, DeCasien and his team, in looking at adults, could not identify the causes of these gene expression differences. The team assigned individuals with XX chromosomes to the female group and XY chromosomes to the male group, but it is unclear whether the expression differences arise in early development or later due to social factors. Tollkuhn and Breedlove wrote that DeCasien’s team “explicitly acknowledge that the sex-related differences reported in their study may originate from differences in socialization and experience.”