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

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

“…Similarly, our analysis of the human GTEx data showed that female-biased genes were enriched for microglial markers (OR = 4.607, p adj = 0.003) and endothelial markers (OR = 17.233, p adj < 0.001) ( Table S8 ), although sex differences in SPVs were only significant for endothelial cells ( p adj < 0.001) ( Figure 3 D; Table S9 ). These findings are consistent with (1) previous analyses of the human GTEx data, 45 (2) the presence of a neurodevelopmental gene co-expression module in postnatal human brains that is enriched for both microglial markers and female-biased genes (ME3), 46 (3) reports of female-biased microglial proportions in adult humans, 47 and (4) our finding that human-macaque conserved female-biased genes (LMM p adj < 0.05 and mashr β < 0; n = 1,105 genes; STAR Methods ) were enriched for immune-related biological processes ( g:Profiler p adj < 0.05) ( Figure 3 E; Tables S10 – S12 ). This shared pattern may reflect evolved sex differences in immune surveillance and response due to the need for birthing people to tolerate an internal, immunologically challenging pregnancy.…”