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

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

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
09 2022
Historique:
received: 07 12 2021
accepted: 24 05 2022
pubmed: 19 8 2022
medline: 16 9 2022
entrez: 18 8 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-022-01104-0 PMID: 35982160 PMC: PMC9653013
pubmed: 35982160
doi: 10.1038/s41588-022-01104-0
pii: 10.1038/s41588-022-01104-0
pmc: PMC9653013
mid: NIHMS1844621
doi:

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1320-1331

Subventions

Organisme : NIMH NIH HHS
ID : R01 MH123184
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH123155
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH099134
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008895
Pays : United States
Organisme : NIEHS NIH HHS
ID : U24 ES028533
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111660
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH097849
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH116999
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD081256
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111662
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH122412
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH123619
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115957
Pays : United States
Organisme : NIMH NIH HHS
ID : R37 MH057881
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH097849
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH129751
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH100027
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH057881
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH129725
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES023513
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111658
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH129724
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111661
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH115957
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH069359
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH094400
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103537
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH109900
Pays : United States
Organisme : NIEHS NIH HHS
ID : R24 ES028533
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD096326
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH100233
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH129722
Pays : United States

Investigateurs

Branko Aleksic (B)
Mykyta Artomov (M)
Elisa Benetti (E)
Monica Biscaldi-Schafer (M)
Anders D Børglum (AD)
Angel Carracedo (A)
Andreas G Chiocchetti (AG)
Hilary Coon (H)
Ryan N Doan (RN)
Montserrat Fernández-Prieto (M)
Christine M Freitag (CM)
Sherif Gerges (S)
Stephen Guter (S)
David M Hougaard (DM)
Christina M Hultman (CM)
Suma Jacob (S)
Miia Kaartinen (M)
Alexander Kolevzon (A)
Itaru Kushima (I)
Terho Lehtimäki (T)
Caterina Lo Rizzo (CL)
Nell Maltman (N)
Marianna Manara (M)
Gal Meiri (G)
Idan Menashe (I)
Judith Miller (J)
Nancy Minshew (N)
Matthew Mosconi (M)
Norio Ozaki (N)
Aarno Palotie (A)
Mara Parellada (M)
Kaija Puura (K)
Abraham Reichenberg (A)
Sven Sandin (S)
Stephen W Scherer (SW)
Sabine Schlitt (S)
Lauren Schmitt (L)
Katja Schneider-Momm (K)
Paige M Siper (PM)
Pål Suren (P)
John A Sweeney (JA)
Karoline Teufel (K)
Maria Del Pilar Trelles (M)
Lauren A Weiss (LA)
Ryan Yuen (R)

Informations de copyright

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

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Auteurs

Jack M Fu (JM)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

F Kyle Satterstrom (FK)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0001-6187-7680

Minshi Peng (M)

Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA.

Harrison Brand (H)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

Ryan L Collins (RL)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.

Shan Dong (S)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

Brie Wamsley (B)

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Lambertus Klei (L)

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Lily Wang (L)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.

Stephanie P Hao (SP)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-3760-8234

Christine R Stevens (CR)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-2621-2234

Caroline Cusick (C)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Mehrtash Babadi (M)

Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Eric Banks (E)

Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Brett Collins (B)

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Sheila Dodge (S)

Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Stacey B Gabriel (SB)

Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Laura Gauthier (L)

Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Samuel K Lee (SK)

Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0001-6733-0547

Lindsay Liang (L)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
ORCID: 0000-0002-9393-2645

Alicia Ljungdahl (A)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

Behrang Mahjani (B)

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Laura Sloofman (L)

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Andrey N Smirnov (AN)

Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0002-4450-0408

Mafalda Barbosa (M)

The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Catalina Betancur (C)

Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France.
ORCID: 0000-0002-3327-4804

Alfredo Brusco (A)

Department of Medical Sciences, University of Torino, Turin, Italy.
Medical Genetics Unit, 'Città della Salute e della Scienza' University Hospital, Turin, Italy.
ORCID: 0000-0002-8318-7231

Brian H Y Chung (BHY)

Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.
ORCID: 0000-0002-7044-5916

Edwin H Cook (EH)

Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
ORCID: 0000-0002-5848-5114

Michael L Cuccaro (ML)

The John P Hussman Institute for Human Genomics, The University of Miami Miller School of Medicine, Miami, FL, USA.

Enrico Domenici (E)

Department of Cellular, Computational and Integrative Biology, , University of Trento, Trento, Italy.
ORCID: 0000-0001-7436-6919

Giovanni Battista Ferrero (GB)

Department of Public Health and Pediatrics, University of Torino, Turin, Italy.

J Jay Gargus (JJ)

Center for Autism Research and Translation, University of California Irvine, Irvine, CA, USA.

Gail E Herman (GE)

The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Irva Hertz-Picciotto (I)

MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.

Patricia Maciel (P)

Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.
ORCID: 0000-0002-0920-6350

Dara S Manoach (DS)

Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0001-9208-1167

Maria Rita Passos-Bueno (MR)

Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.

Antonio M Persico (AM)

Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy.

Alessandra Renieri (A)

Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Medical Genetics, , University of Siena, Siena, Italy.
Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

James S Sutcliffe (JS)

Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
ORCID: 0000-0001-5200-6007

Flora Tassone (F)

MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.
Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA.

Elisabetta Trabetti (E)

Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy.

Gabriele Campos (G)

Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
ORCID: 0000-0002-0470-3382

Simona Cardaropoli (S)

Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
ORCID: 0000-0002-8927-8900

Diana Carli (D)

Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
ORCID: 0000-0001-5690-6504

Marcus C Y Chan (MCY)

Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Chiara Fallerini (C)

Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Medical Genetics, , University of Siena, Siena, Italy.

Elisa Giorgio (E)

Department of Medical Sciences, University of Torino, Turin, Italy.

Ana Cristina Girardi (AC)

Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
ORCID: 0000-0001-6531-501X

Emily Hansen-Kiss (E)

Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, USA.

So Lun Lee (SL)

Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Carla Lintas (C)

Service for Neurodevelopmental Disorders, University Campus Bio-medico of Rome, Rome, Italy.

Yunin Ludena (Y)

MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.

Rachel Nguyen (R)

Center for Autism Research and Translation, University of California Irvine, Irvine, CA, USA.

Lisa Pavinato (L)

Department of Medical Sciences, University of Torino, Turin, Italy.
ORCID: 0000-0002-7630-8365

Margaret Pericak-Vance (M)

The John P Hussman Institute for Human Genomics, The University of Miami Miller School of Medicine, Miami, FL, USA.
ORCID: 0000-0001-7283-8804

Isaac N Pessah (IN)

MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.
Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA.

Rebecca J Schmidt (RJ)

MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.
ORCID: 0000-0003-1582-2747

Moyra Smith (M)

Center for Autism Research and Translation, University of California Irvine, Irvine, CA, USA.

Claudia I S Costa (CIS)

Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.

Slavica Trajkova (S)

Department of Medical Sciences, University of Torino, Turin, Italy.

Jaqueline Y T Wang (JYT)

Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.

Mullin H C Yu (MHC)

Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.

David J Cutler (DJ)

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

Silvia De Rubeis (S)

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
ORCID: 0000-0001-9383-6883

Joseph D Buxbaum (JD)

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.
ORCID: 0000-0001-8898-8313

Mark J Daly (MJ)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.
Harvard Medical School, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. mjdaly@atgu.mgh.harvard.edu.
ORCID: 0000-0002-0949-8752

Bernie Devlin (B)

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. devlinbj@upmc.edu.
ORCID: 0000-0003-2524-4290

Kathryn Roeder (K)

Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA. roeder@andrew.cmu.edu.
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA. roeder@andrew.cmu.edu.
ORCID: 0000-0002-8869-6254

Stephan J Sanders (SJ)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. Stephan.Sanders@ucsf.edu.
ORCID: 0000-0001-9112-5148

Michael E Talkowski (ME)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. MTALKOWSKI@mgh.harvard.edu.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. MTALKOWSKI@mgh.harvard.edu.
Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.
ORCID: 0000-0003-2889-0992

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles généralisés du développement de l'enfant › Trouble du spectre autistique › Rare coding variation provides insight into...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles généralisés du développement de l'enfant › Trouble du spectre autistique › Trouble autistique › Rare coding variation provides insight into...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › Rare coding variation provides insight into...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Rare coding variation provides insight into...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Rare coding variation provides insight into...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Rare coding variation provides insight into...