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

By F. Satterstrom, J. Kosmicki, Jiebiao Wang, M. Breen, Silvia De Rubeis, Joon-Yong An, Minshi Peng, Ryan L. Collins, J. Grove, L. Klei and 180 more. Cell, 2019

2,000 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/acf92569ed6ca02dbca6a24c65a35bbfae13170c

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In Genetics

1. G. Consortium
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Citations in the corpus

• Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex (2020, background): “​ ​(Satterstrom et al., 2020)​, which identified 102 genes with ASD-associated variants.”
• Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders (2019, background): “In supplementary analyses, we did not find evidence of significant overrepresentation of genes related to pleiotropic SNPs identified here among previously defined genomic disorder regions or genes associated with neurodevelopmental disorders from rare variant studies (including ASD, intellectual di”
• Rare coding variants in 10 genes confer substantial risk for schizophrenia (2022, neutral): “Missense, MPC 2–3 (10) Missense, MPC > 3 (1) Missense, MPC > 3 (3)”