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

Autism Sequencing Consortium, Suma Jacob

Research output: Contribution to journalArticlepeer-review

1100 Scopus citations


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 (US)
Pages (from-to)568-584.e23
Issue number3
StatePublished - Feb 6 2020

Bibliographical note

Funding Information:
We thank the families who participated in this research, without whose contributions genetic studies would be impossible. This study was supported by the AMED ( JP19dm0107087 to B.A. and N.O.), Autism Science Foundation (to S.J.S., S.L.B., and E.B.R.), NHGRI ( HG008895 to M.J.D. and HG002295 to R.C.), NIMH ( MH111658 and MH057881 to B.D., MH111661 and MH100233-03S1 to J.D.B., R01 MH109900 to K.R., MH115957 to M.E.T., MH111660 to M.J.D., and MH111662 to S.J.S. and M.W.S.), NSF ( GRFP 2017240332 to R.C.), the Seaver Foundation (to J.D.B. and S.D.R.), and the Simons Foundation ( SF402281 to S.J.S., M.W.S., B.D., and K.R. and SF573206 to M.E.T.). Funding for individual cohorts is detailed further in the STAR Methods . We thank Tom Nowakowski (UCSF) for facilitating access to the single-cell gene expression data.

Publisher Copyright:
© 2020 Elsevier Inc.


  • autism spectrum disorder
  • cell type
  • cytoskeleton
  • excitatory neurons
  • excitatory-inhibitory balance
  • exome sequencing
  • genetics
  • inhibitory neurons
  • liability
  • neurodevelopment

PubMed: MeSH publication types

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


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