Over 3,000 Genes Linked to Sex-Based Differences in the Brain

Why do some brain disorders affect men and women differently?

Researchers at the National Institutes of Health conducted a large-scale single-cell analysis of the human cortex, uncovering over 3,000 genes with sex-biased activity.

Understanding why sex influences brain health risks

Men and women face significantly different risks for brain-related health conditions. Disorders such as ADHD and schizophrenia appear more frequently in males, while females are more likely to experience depression or Alzheimer’s disease. These patterns are consistent across different cultures and developmental stages, suggesting that biological factors, such as sex, play a fundamental role in how our brains function. While social influences are important, researchers suspect that differences in gene activity drive these sex-based differences in brain health.

Understanding these differences at a molecular level has been challenging; scientists have struggled to pinpoint exactly how sex influences the brain's inner workings.

“Most current knowledge of molecular brain sex differences relies on studies of bulk tissue or isolated brain regions,” said the authors.

Researchers in the new study aimed to create a high-resolution, single-cell map of gene activity across the human cerebral cortex. By examining individual cells rather than whole chunks of tissue, they hoped to connect molecular variation to physical brain structure.

Mapping how sex affects gene activity in brain cells

The team used single-nucleus RNA sequencing to analyze 169 tissue samples from 30 adult donors, consisting of 15 males and 15 females. They chose six specific regions of the cerebral cortex to focus on, based on brain imaging data showing varying degrees of physical differences between the biological sexes. By comparing regions with known anatomical differences to those without, the team could determine how molecular activity aligns with physical brain structure.

While the sex-based differences were subtle, they appeared in thousands of genes throughout the brain. The team identified over 3,000 genes that showed sex-biased activity in at least one brain region. Among these, a core group of 133 genes showed consistent differences across all studied regions and cell types.

Although the biggest differences appeared in genes on the sex chromosomes, most of the variation occurred in autosomal genes. These are genes not directly linked to sex chromosomes but appear to be influenced by sex steroid hormones.

The study found that these molecular differences were not uniform and were most pronounced in the fusiform cortex, a region linked to social processing and visual recognition. Within these regions, specific cell types such as oligodendrocytes, astrocytes, and excitatory neurons showed the most significant sex-biased activity.

The future of sex-specific treatments for brain disorders

The team discovered a significant overlap between sex-biased genes and genetic markers for brain disorders, including risks for ADHD, schizophrenia, and neurodegenerative conditions.

By identifying which genes are more active in one sex, scientists can better understand why certain treatments work differently for men and women, which could lead to more effective, sex-specific therapies for psychiatric and neurological conditions.

However, since the data comes from adult brain tissue, it is difficult to separate innate biology from a lifetime of experience. Environment and socialization can change how genes are expressed over many years.

“Future studies will be needed to illuminate when sex differences emerge during development and whether they are consistent across populations,” said the authors.

Investigating prenatal gene activity would allow researchers to see how hormones and chromosomes shape the brain before external influences take hold, ruling out the impact of social factors.

Reference: DeCasien AR, Auluck P, Liu S, et al. Sex effects on gene expression across the human cerebral cortex at cell type resolution. Science. 2026;392(6795):eaea9063. doi: 10.1126/science.aea9063

This article is a rework of a press release issued by the American Association for the Advancement of Science. Material has been edited for length and content.