Publication
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.
Satterstrom F Kyle, Kosmicki Jack A, Wang Jiebiao, Breen Michael S, De Rubeis Silvia, An Joon-Yong, Peng Minshi, Collins Ryan, Grove Jakob, Klei Lambertus, Stevens Christine, Reichert Jennifer, Mulhern Maureen S, Artomov Mykyta, Gerges Sherif, Sheppard Brooke, Xu Xinyi, Bhaduri Aparna, Norman Utku, Brand Harrison, Schwartz Grace, Nguyen Rachel, Guerrero Elizabeth E, Dias Caroline, Autism Sequencing Consortium, iPSYCH-Broad Consortium, Betancur Catalina, Cook Edwin H, Gallagher Louise, Gill Michael, Sutcliffe James S, Thurm Audrey, Zwick Michael E, Børglum Anders D, State Matthew W, Cicek A Ercument, Talkowski Michael E, Cutler David J, Devlin Bernie, Sanders Stephan J, Roeder Kathryn, Daly Mark J, Buxbaum Joseph D
# Autism Spectrum Disorder
This large-scale exome sequencing study examined 35,584 samples (11,986 with autism spectrum disorder) to identify genetic risk factors for ASD. The researchers identified 102 risk genes using an integrated analytical framework combining de novo and case-control rare variants. Notably, 49 genes showed higher frequencies of disruptive de novo variants in severe neurodevelopmental delay cases, while 53 were enriched in ASD cases, with individuals carrying mutations in these distinct gene groups displaying different phenotypes.
The identified risk genes, primarily expressed early in brain development, predominantly function in gene expression regulation and neuronal communication—mechanisms reflecting both neurodevelopmental and neurophysiological changes. Single-cell analysis of human cortical tissue revealed that risk gene expression is enriched in excitatory and inhibitory neuronal lineages. These findings support the hypothesis that multiple distinct genetic pathways converge on excitatory-inhibitory imbalance as an underlying mechanism in autism, and 13 identified genes overlap with loci recurrently affected by copy number variants in ASD.
Abstract
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.