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

doi:10.1038/s41588-022-01104-0

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 journal › Article › peer-review

238 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	1320-1331
Number of pages	12
Journal	Nature Genetics
Volume	54
Issue number	9
DOIs	https://doi.org/10.1038/s41588-022-01104-0
State	Published - 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.

Keywords

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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10.1038/s41588-022-01104-0

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@article{0a4fe519aba14bb7a2e9aab7af159617,

title = "Rare coding variation provides insight into the genetic architecture and phenotypic context of autism",

abstract = "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.",

keywords = "Autism Spectrum Disorder/genetics, Autistic Disorder/genetics, DNA Copy Number Variations/genetics, Genetic Predisposition to Disease, Humans, Mutation",

author = "{The Autism Sequencing Consortium (ASC)} and {Broad Institute Center for Common Disease Genomics (Broad-CCDG)} and {iPSYCH-BROAD Consortium} and Fu, {Jack M.} and Satterstrom, {F. Kyle} and Minshi Peng and Harrison Brand and Collins, {Ryan L.} and Shan Dong and Brie Wamsley and Lambertus Klei and Lily Wang and Hao, {Stephanie P.} and Stevens, {Christine R.} and Caroline Cusick and Mehrtash Babadi and Eric Banks and Brett Collins and Sheila Dodge and Gabriel, {Stacey B.} and Laura Gauthier and Lee, {Samuel K.} and Lindsay Liang and Alicia Ljungdahl and Behrang Mahjani and Laura Sloofman and Smirnov, {Andrey N.} and Mafalda Barbosa and Catalina Betancur and Alfredo Brusco and Chung, {Brian H.Y.} and Cook, {Edwin H.} and Cuccaro, {Michael L.} and Enrico Domenici and Ferrero, {Giovanni Battista} and Gargus, {J. Jay} and Herman, {Gail E.} and Irva Hertz-Picciotto and Patricia Maciel and Manoach, {Dara S.} and Passos-Bueno, {Maria Rita} and Persico, {Antonio M.} and Alessandra Renieri and Sutcliffe, {James S.} and Flora Tassone and Elisabetta Trabetti and Gabriele Campos and Simona Cardaropoli and Diana Carli and Chan, {Marcus C.Y.} and Chiara Fallerini and Elisa Giorgio and Suma Jacob",

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: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01104-0",

language = "English (US)",

volume = "54",

pages = "1320--1331",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

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TY - JOUR

T1 - Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

AU - The Autism Sequencing Consortium (ASC)

AU - Broad Institute Center for Common Disease Genomics (Broad-CCDG)

AU - iPSYCH-BROAD Consortium

AU - Fu, Jack M.

AU - Satterstrom, F. Kyle

AU - Peng, Minshi

AU - Brand, Harrison

AU - Collins, Ryan L.

AU - Dong, Shan

AU - Wamsley, Brie

AU - Klei, Lambertus

AU - Wang, Lily

AU - Hao, Stephanie P.

AU - Stevens, Christine R.

AU - Cusick, Caroline

AU - Babadi, Mehrtash

AU - Banks, Eric

AU - Collins, Brett

AU - Dodge, Sheila

AU - Gabriel, Stacey B.

AU - Gauthier, Laura

AU - Lee, Samuel K.

AU - Liang, Lindsay

AU - Ljungdahl, Alicia

AU - Mahjani, Behrang

AU - Sloofman, Laura

AU - Smirnov, Andrey N.

AU - Barbosa, Mafalda

AU - Betancur, Catalina

AU - Brusco, Alfredo

AU - Chung, Brian H.Y.

AU - Cook, Edwin H.

AU - Cuccaro, Michael L.

AU - Domenici, Enrico

AU - Ferrero, Giovanni Battista

AU - Gargus, J. Jay

AU - Herman, Gail E.

AU - Hertz-Picciotto, Irva

AU - Maciel, Patricia

AU - Manoach, Dara S.

AU - Passos-Bueno, Maria Rita

AU - Persico, Antonio M.

AU - Renieri, Alessandra

AU - Sutcliffe, James S.

AU - Tassone, Flora

AU - Trabetti, Elisabetta

AU - Campos, Gabriele

AU - Cardaropoli, Simona

AU - Carli, Diana

AU - Chan, Marcus C.Y.

AU - Fallerini, Chiara

AU - Giorgio, Elisa

AU - Jacob, Suma

N1 - 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.

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Autism Spectrum Disorder/genetics

KW - Autistic Disorder/genetics

KW - DNA Copy Number Variations/genetics

KW - Genetic Predisposition to Disease

KW - Humans

KW - Mutation

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UR - http://www.scopus.com/inward/citedby.url?scp=85136292014&partnerID=8YFLogxK

U2 - 10.1038/s41588-022-01104-0

DO - 10.1038/s41588-022-01104-0

M3 - Article

C2 - 35982160

AN - SCOPUS:85136292014

SN - 1061-4036

VL - 54

SP - 1320

EP - 1331

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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