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

Cell. 2020 Feb 6;180(3):568-584.e23. doi: 10.1016/j.cell.2019.12.036. Epub 2020 Jan 23.

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.

Keywords: autism spectrum disorder; cell type; cytoskeleton; excitatory neurons; excitatory-inhibitory balance; exome sequencing; genetics; inhibitory neurons; liability; neurodevelopment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Autistic Disorder / genetics*
  • Case-Control Studies
  • Cell Lineage
  • Cerebral Cortex / growth & development*
  • Cohort Studies
  • Exome
  • Female
  • Gene Expression Regulation, Developmental*
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mutation, Missense
  • Neurobiology / methods*
  • Neurons / metabolism
  • Phenotype
  • Sex Factors
  • Single-Cell Analysis / methods
  • Whole Exome Sequencing / methods*