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

Autism Sequencing Consortium, F Kyle Satterstrom, Jack A Kosmicki, Jiebiao Wang, Michael S Breen, Silvia De Rubeis, Joon-Yong An, Minshi Peng, Ryan Collins, Jakob Grove, Lambertus Klei, Christine Stevens, Jennifer Reichert, Maureen S Mulhern, Mykyta Artomov, Sherif Gerges, Brooke Sheppard, Xinyi Xu, Aparna Bhaduri, Utku NormanHarrison Brand, Grace Schwartz, Rachel Nguyen, Elizabeth E Guerrero, Caroline Dias, Catalina Betancur, Edwin H Cook, Louise Gallagher, Michael Gill, James S Sutcliffe, Audrey Thurm, Michael E Zwick, Anders D Børglum, Matthew W State, A Ercument Cicek, Michael E Talkowski, David J Cutler, Bernie Devlin, Stephan J Sanders, Kathryn Roeder, Mark J Daly, Joseph D Buxbaum, Terho Lehtimäki

Research output: Contribution to journalArticleScientificpeer-review

219 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)568-584.e23
Issue number3
Publication statusPublished - 2020
Publication typeA1 Journal article-refereed


  • 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

Publication forum classification

  • Publication forum level 3

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