Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Date
2020-02-06
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Source Title
Cell
Print ISSN
0092-8674
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Publisher
Elsevier
Volume
180
Issue
3
Pages
568 - 5.84E+025
Language
English
Type
Article
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Abstract

We present the largest exome sequencing study ofautism spectrum disorder (ASD) to date (n = 35,584total samples, 11,986 with ASD). Using an enhancedanalytical framework to integratedenovoand case-control rare variation, we identify 102 risk genes at afalse discovery rate of 0.1 or less. Of these genes, 49show higher frequencies of disruptivedenovovari-ants in individuals ascertained to have severe neuro-developmental delay, whereas 53 show higher fre-quencies in individuals ascertained to have ASD;comparing ASD cases with mutations in thesegroups reveals phenotypic differences. Expressedearly in brain development, most risk genes haveroles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelop-mental and neurophysiological changes), and 13 fallwithin loci recurrently hit by copy number variants.In cells from the human cortex, expression of riskgenes is enriched in excitatory and inhibitoryneuronal lineages, consistent with multiple paths toan excitatory-inhibitory imbalance underlying ASD.

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Keywords
Autism spectrum disorder, Cell type, Cytoskeleton, Excitatory neurons, Excitatory-inhibitory balance, Exome sequencing, Genetics, Inhibitory neurons, Liability
Citation
Published Version (Please cite this version)