Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

The Autism Sequencing Consortium (ASC), Broad Institute Center for Common Disease Genomics (Broad-CCDG), iPSYCH-BROAD Consortium

Research output: Contribution to journalArticlepeer-review

122 Scopus citations


Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Original languageEnglish (US)
Pages (from-to)1320-1331
Number of pages12
JournalNature Genetics
Issue number9
StatePublished - Sep 2022

Bibliographical note

Funding Information:
We thank all of the individuals who participated in this research. We also thank all contributing investigators to the consortia datasets used here from the Autism Sequencing Consortium (ASC), the Simons Simplex Collection (SSC), Simons Powering Autism Research for Knowledge (SPARK) project, the iPSYCH project, the Deciphering Developmental Disorders (DDD) study and Schizophrenia Exome Meta-Analysis (SCHEMA). This work was supported by grants from the Simons Foundation for Autism Research Initiative (SSC-ASC Genomics Consortium 574598 to S.J.S., 575097 to B.D. and K.R., 573206 to M.E.T. and M.J.D., 571009 to J.D.); the SPARK project and SPARK analysis projects (606362 and 608540 to M.E.T., M.J.D., J.D.B., B.D., K.R. and S.J.S.); SFARI (736613 and 647371 to S.J.S.), NHGRI (HG008895 to M.J.D., S.G. and M.E.T.), NIMH (MH115957 and MH123155 to M.E.T., MH111658 and MH057881 to B.D., MH097849, MH111661 and MH100233 to J.D.B., MH109900 and MH123184 to K.R., MH111660 and MH129722 to M.J.D. and MH111662 and MH100027 to S.J.S.), NICHD (HD081256 and HD096326 to M.E.T.), AMED (JP21WM0425007 to N.O.) and the Beatrice and Samuel Seaver Foundation. J.M.F. was supported by an Autism Speaks Postdoctoral Fellowship and R.L.C. was supported by NSF GRFP 2017240332. E.D. was supported by Fondazione Italiana Autismo (FIA-2018/53).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.


  • Autism Spectrum Disorder/genetics
  • Autistic Disorder/genetics
  • DNA Copy Number Variations/genetics
  • Genetic Predisposition to Disease
  • Humans
  • Mutation

PubMed: MeSH publication types

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


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