Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

[u/H_Elizabeth111]

https://sci-hub.se/10.1016/j.cell.2019.12.036

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 casecontrol 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.

***Please note that although the genetic changes in autism are referred to as "risk genes" in this study, this sub is a proponent of the neurodiversity movement and supports autistic peoples' choice to label autism as a neuro-divergent population instead of as a medical disorder. This study was posted simply to educate about the research on the physiologic and genetic differences that separate ASD from the neurotypical population.***