ABSTRACT
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, although 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 2 independent bulk RNA sequencing datasets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess the 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 identified 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, did not preferentially overlap with sex-DEGs. We identified 1 male-specific co-expression module enriched for immune signaling that is unique to 1 input dataset. Conclusions: Sex-differential gene expression is limited in prenatal human cortex tissue, although meta-analysis of large datasets allows for the identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in the prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, at other developmental stages, or in specific cell types, or may involve mechanisms that act downstream from mutation-carrying genes.
Males are more commonly diagnosed with autism spectrum disorder than females, and sex differences in brain development may contribute to this difference. Here, we define differences in gene expression patterns between males and females in human prenatal brain tissue from 273 donors to identify 101 genes that are expressed at different levels in males and females and gene sets that show sex-specific expression correlations. Genes with autism-associated DNA variants and genes with altered expression in autism do not preferentially overlap with sex-differential genes, suggesting that sex-differential biology may influence autism risk mechanisms in other brain regions, at other developmental stages, or in specific cell types.
ABSTRACT
Autism spectrum disorder (ASD) is consistently diagnosed 3 to 5 times more frequently in males than females, a dramatically sex-biased prevalence that suggests the involvement of sex-differential biological factors in modulating risk. The genomic scale of transcriptomic analyses of human brain tissue can provide an unbiased approach for identifying genes and associated functional processes at the intersection of sex-differential and ASD-impacted neurobiology. Several studies characterizing gene expression changes in the ASD brain have been published in recent years with increasing sample size and cellular resolution. These studies report several convergent patterns across data sets and genetically heterogeneous samples in the ASD brain, including elevated expression of gene sets associated with glial and immune function, and reduced expression of gene sets associated with neuronal and synaptic functions. Assessment of neurotypical cortex tissue has reported parallel patterns by sex, with male-elevated expression of overlapping sets of glial/immune-related genes and female-biased expression of neuron-associated genes, suggesting potential roles for these cell types in sex-differential ASD risk mechanisms. However, validating and further exploring these mechanisms is challenged by the available data, as existing studies of ASD brain include a limited number of female ASD donors and focus predominantly on cortex regions not known to show pronounced sex-differential morphology or function. With this review, we summarize convergent findings from several landmark studies of the transcriptome in ASD brain and their relationship to sex-differential gene expression, and we discuss limitations and remaining questions regarding transcriptomic analysis of sex differences in ASD.
