Sexual dimorphism in fetal brain gene co-expression networks as a possible etiological factor of sex-biased autism prevalence

Autism spectrum disorder (ASD) affects more males than females in an approximate ratio of 4:1, yet the biological bases of this imbalance remain unclear. Here, we explored the hypothesis that part of the male-biased vulnerability could arise from sex-specific baseline organization of gene regulatory networks during fetal brain development. To test this, we analyzed post-mortem cortical samples spanning a critical spatiotemporal window implicated in ASD pathophysiology and built sex-specific and consensus co-expression networks using weighted gene co-expression network analysis (WGCNA). Four modules were enriched for ASD-associated genes: two related to transcriptional regulation and two associated with neurodevelopment and synaptic function. Despite an overall conserved modular constitution between males and females, sex-dependent differences in levels of expression, module topology and inter-modular coordination were observed. Interestingly, the distribution of rare de novo variants found in mutation-intolerant genes in ASD individuals diverged across modules between males and females. Altogether, our results indicate that male and female fetal brains share core ASD-related molecular programs, but differ in their structural organization. These sex-specific regulatory contexts likely modulate the functional impact of ASD-risk variants and contribute to the marked sex bias in ASD susceptibility.