부산대학교 도서관

Keywords autism spectrum disorder; exome sequencing; genetics; neurodevelopment; liability; cell type; cytoskeleton; excitatory neurons; inhibitory neurons; excitatory-inhibitory balance Highlights * 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR [less than or equal to] 0.1) * Most are expressed and enriched early in excitatory and inhibitory neuronal lineages * Most affect synapses or regulate other genes; how these roles dovetail is unknown * Some ASD genes alter early development broadly, others appear more specific to ASD Summary We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 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.