Transcriptomic convergence and the female protective effect in autism

Autism spectrum disorder (ASD) is highly heritable, and mutations in hundreds of genes have been implicated as individually rare causes of ASD^1-3. Understanding how disruptions to these functionally diverse genes lead to the core features of ASD remains a major challenge⁴. Moreover, ASD is three- to four-fold more common in male than in female individuals⁵, and female autistic people tend to carry more autosomal risk alleles for ASD compared with their male counterparts^6,7; however, the biological basis of this 'female protective effect' (FPE) has remained unknown^8,9. Here we show that individual perturbations of 18 ASD genes in human neural progenitor cells converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network enabled identification of central transcriptional regulators that drive this transcriptomic convergence, including prominent ASD gene CHD8 and candidates including REST. Furthermore, X-linked transcription factor ZFX, which is expressed from both the active and the inactive X chromosomes in female individuals¹⁰, emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in the female brain can buffer damaging mutations in diverse ASD genes, contributing to the female protective effect. Together, these results show how key gene regulatory networks can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.