An exome sequencing study of autism spectrum disorder (ASD) identified 102 risk genes at a false discovery rate of 0.1 or less. The study included 35,584 total samples, 11,986 with ASD, and used an enhanced analytical framework to integrate de novo and case-control rare variation. 49 of the risk genes show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD. ASD-associated genes are distributed across a spectrum of phenotypes and selective pressure. The findings form an important step forward in elucidating the neurobiology of ASD. Source: https://www.cell.com/
