Relationship between sex biases in gene expression and sex biases in autism and Alzheimer’s disease

Abstract

Background

Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions.

Methods

In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks.

Results

We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case–control gene expression studies suggests a female molecular predisposition towards Alzheimer’s disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis.

Conclusion

Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s13293-024-00622-2.

Highlights

• Numerous but small autosomal sex differences in expression exist in all brain regions tested.

• Autosomal genes with enriched expression in males are enriched in neuronal pathways.

• Autosomal genes with enriched expression in females are enriched with immune system functions.

• Integration with single-nucleus datasets suggest these differences are more likely related to cell state differences than cell number differences.

• The female cortex shows an enrichment of genes expressed in Alzheimer’s disease brains.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13293-024-00622-2.

Abstract

We sought to understand why females have higher rates of Alzheimer’s disease, and males have higher rates of autism. One idea was that the female brain at baseline may be more similar to an Alzheimer’s brain, so it is easier for them to shift into that state (likewise, males may be more similar to autism). To test this, we examined gene expression differences between brains of biological males and biological females. While all people have the same ~ 25,000 genes, each gene can be on or off (‘expressed’) to different extents. Overall, we found that there were differences in gene expression between males and females in all brain regions tested but more differences in some brain regions than others. By looking at the role of these genes we estimate that female immune system processes might be more active in the brain. We also found female brain gene expression looked slightly more like people with Alzheimer’s compared to people without Alzheimer’s, which may explain why females get Alzheimer’s disease more easily. However, the male brain gene expression did not look more like autism, suggesting that the reason males have higher rates of autism is complex and needs further investigation.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13293-024-00622-2.