RT Journal Article SR Electronic T1 Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.05.23.112623 DO 10.1101/2020.05.23.112623 A1 Vahid H. Gazestani A1 Austin WT Chiang A1 Eric Courchesne A1 Nathan E. Lewis YR 2020 UL http://biorxiv.org/content/early/2020/05/26/2020.05.23.112623.abstract AB Numerous genes are associated with autism spectrum disorder (ASD); however, it remains unclear how most ASD risk genes influence neurodevelopment and result in similar traits. Recent genetic models of complex traits suggest non-tissue-specific genes converge on core disease genes; so we analyzed ASD genetics in this context. We found ASD risk genes partition cleanly into broadly-expressed and brain-specific genes. The two groups show sequential roles during neurodevelopment with broadly-expressed genes modulating chromatin remodeling, proliferation, and cell fate, while brain-specific risk genes are involved in neural maturation and synapse functioning. Broadly-expressed risk genes converge onto brain-specific risk genes and core neurodevelopmental genes through regulatory networks including PI3K/AKT, RAS/ERK, and WNT/β-catenin signaling pathways. Broadly-expressed and brain-specific risk genes show unique properties, wherein the broadly-expressed risk gene network is expressed prenatally and conserved in non-neuronal cells like microglia. However, the brain-specific gene network expression is limited to excitatory and inhibitory neurons, spanning prenatal to adulthood. Furthermore, the two groups are linked differently to comorbidities associated with ASD. Collectively, we describe here the organization of the genetic architecture of ASD as a hierarchy of broadly-expressed and brain-specific genes that disrupt successive stages of core neurodevelopmental processes.Competing Interest StatementThe authors have declared no competing interest.