Transcriptomic Convergence and the Female Protective Effect in Autism

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by deficits in social communication as well as restricted and/or repetitive behaviors. ASD is highly heritable¹, with a complex genetic architecture: large-scale studies have identified dosage-altering copy number variants (CNV) and single nucleotide variants (SNV) that implicate hundreds of genes as individually rare causes of ASD (ASD genes)^2-4, with common variation at multiple loci also contributing substantially to risk⁵. Understanding how disruptions to these functionally diverse genes lead to the shared core features of ASD remains a major challenge⁶. Moreover, ASD is three- to four-fold more common in males than females^7,8, and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males^9-13, but the biological basis of this "female protective effect" (FPE) is unknown^14,15. Here we show that individual perturbations of 18 ASD genes converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST, that drive this transcriptomic convergence in ASD. Furthermore, the X-linked transcription factor ZFX, which is expressed from both the active and the "inactive" X chromosomes in females¹⁶, emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.