Transcriptomic Convergence and the Female Protective Effect in Autism [RNA-Seq, CRISPR-Cas13 KD)

ASD is highly heritable, 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), with common variation at multiple loci also contributing substantially to risk.

Understanding how disruptions to these functionally diverse genes lead to the shared core features of ASD remains a major challenge. Moreover, ASD is three- to four-fold more common in males than females, and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males, but the biological basis of this “female protective effect” (FPE) is unknown. 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.