Sex-differential gene expression in developing human cortex and its intersection with autism risk pathways

Background Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in the brain can indicate possible molecular and cellular mechanisms involved, though transcriptomic sex differences during human prenatal cortical development have been incompletely characterized, primarily due to small sample sizes. Methods We performed a meta-analysis of sex-differential expression and co-expression network analysis in two independent bulk RNA-seq data sets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess intersection between neurotypical sex differences and neuropsychiatric disorder biology, we tested for enrichment of ASD-associated risk genes and expression changes, neuropsychiatric disorder risk genes, and cell type markers within identified sex-differentially expressed genes (sex-DEGs) and sex-differential co-expression modules. Results We identify 101 significant sex-DEGs, including Y chromosome genes, genes impacted by X chromosome inactivation, and autosomal genes. Known ASD risk genes, implicated by either common or rare variants, do not preferentially overlap with sex-DEGs. We identify one male-specific co-expression module enriched for immune signaling that is unique to one input data set. Conclusions Sex-differential gene expression is limited in prenatal human cortex tissue, though meta-analysis of large data sets allows for identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, developmental stages, in specific cell types, or may involve mechanisms acting downstream from mutation-carrying genes.