Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

The SPARK Consortium

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10−6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10−6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Original languageEnglish (US)
Pages (from-to)1305-1319
Number of pages15
JournalNature Genetics
Volume54
Issue number9
DOIs
StatePublished - Sep 2022

Bibliographical note

Funding Information:
We are extremely grateful to the thousands of individuals and families who are participating in this study. We thank the sites, staff and volunteers of the SPARK Clinical Site Network and SFARI for their invaluable contributions. We are grateful to the many ASD advocacy and service organizations that have helped us inform the community about SPARK, including the Autism Society of America and its affiliates, the Global and Regional Autism Spectrum Partnership (GRASP), Autism Speaks, and the Autism Science Foundation. We thank the members of SPARK’s Community Advisory Council for providing feedback and advice. We thank members of our Scientific Advisory Board and SFARI scientists for advice on our protocol and participant outreach and retention strategies. Our de novo analyses involved primary data from SSC and results from published ASD studies, including ASC and MSSNG, and our case-control analysis used published population controls from gnomAD (exome v2.1.1, non-neuro subset) and TOPMed (WGS, freeze 8). Approved researchers can obtain the SPARK population dataset described in this study by applying at https://base.sfari.org . The SPARK initiative is funded by the Simons Foundation as part of SFARI. This research was supported, in part, by a grant from the National Institute of Mental Health (NIMH R01MH101221) and grants from the Simons Foundation (SFARI nos. 608045 and 810018EE) to E.E.E., a grant from the National Institutes of Health (NIH R01GM120609) and from the Simons Foundation (SFARI no. 606450) to Y.S., a grant from the Simons Foundation (SFARI no. 644038) to B.J.O. and J.J.M., a grant from the National Institute of Mental Health to T.N.T. (NIMH 1K99MH117165), and grants MH105527 and DC014489 from the National Institute of Health to J.J.M. E.E.E. is an investigator of the Howard Hughes Medical Institute.

Funding Information:
We are extremely grateful to the thousands of individuals and families who are participating in this study. We thank the sites, staff and volunteers of the SPARK Clinical Site Network and SFARI for their invaluable contributions. We are grateful to the many ASD advocacy and service organizations that have helped us inform the community about SPARK, including the Autism Society of America and its affiliates, the Global and Regional Autism Spectrum Partnership (GRASP), Autism Speaks, and the Autism Science Foundation. We thank the members of SPARK’s Community Advisory Council for providing feedback and advice. We thank members of our Scientific Advisory Board and SFARI scientists for advice on our protocol and participant outreach and retention strategies. Our de novo analyses involved primary data from SSC and results from published ASD studies, including ASC and MSSNG, and our case-control analysis used published population controls from gnomAD (exome v2.1.1, non-neuro subset) and TOPMed (WGS, freeze 8). Approved researchers can obtain the SPARK population dataset described in this study by applying at https://base.sfari.org. The SPARK initiative is funded by the Simons Foundation as part of SFARI. This research was supported, in part, by a grant from the National Institute of Mental Health (NIMH R01MH101221) and grants from the Simons Foundation (SFARI nos. 608045 and 810018EE) to E.E.E., a grant from the National Institutes of Health (NIH R01GM120609) and from the Simons Foundation (SFARI no. 606450) to Y.S., a grant from the Simons Foundation (SFARI no. 644038) to B.J.O. and J.J.M., a grant from the National Institute of Mental Health to T.N.T. (NIMH 1K99MH117165), and grants MH105527 and DC014489 from the National Institute of Health to J.J.M. E.E.E. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Autism Spectrum Disorder/genetics
  • Autistic Disorder/genetics
  • Exome/genetics
  • Forkhead Transcription Factors/genetics
  • Genetic Predisposition to Disease
  • Humans
  • Mutation
  • Repressor Proteins/genetics
  • Whole Exome Sequencing

PubMed: MeSH publication types

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

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