Identification of common genetic risk variants for autism spectrum disorder

Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium; BUPGEN; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; 23andMe Research Team

doi:10.1038/s41588-019-0344-8

Identification of common genetic risk variants for autism spectrum disorder

Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium
, BUPGEN
, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
, 23andMe Research Team

The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Aarhus University
Massachusetts General Hospital
Broad Institute
Charité – Universitätsmedizin Berlin
University of Würzburg
Karolinska Institutet
University of North Carolina at Chapel Hill
University of Oslo
Cardiff University
Icahn School of Medicine at Mount Sinai
Statens Serum Institut
University of Pittsburgh
MHC Sct. Hans
Genomics
Vertex Pharmaceuticals
University of Helsinki
Max Planck Institute for Psycholinguistics
University of Bristol
Radboud University Nijmegen
University of Amsterdam
Wellcome Trust Sanger Institute
Harvard University
Carnegie Mellon University
VA Medical Center
The State Diagnostic and Counselling Centre
deCODE Genetics
University of Iceland
University of Queensland
University of Edinburgh
Adelaide University
Max Planck Institute of Psychiatry
Munich Cluster for Systems Neurology (SyNergy)
Virginia Commonwealth University
VU University Medical Center
Virginia Institute for Psychiatric and Behavior Genetics
Emory University
European Molecular Biology Laboratory
University of Lausanne
King's College London
Queensland Institute of Medical Research
Duke University
University of Bonn
Erasmus University Rotterdam
Dokuz Eylul University
University of British Columbia
Massachusetts Institute of Technology
University of Basel
Heidelberg University
Trinity College Dublin
Johns Hopkins University
Newcastle University
University of Copenhagen
Mental Health Services Capital Region of Denmark
H. Lundbeck A/S
The University of Sydney
University of Greifswald
F. Hoffmann-La Roche AG
Kaiser Permanente
University of Southern California
Brigham and Women’s Hospital
Boston Children's Hospital
University of Oxford
Swiss Institute of Bioinformatics
National Health Service Scotland
Columbia University
Queensland University of Technology
Children’s Health Queensland
University of Tartu
German Centre for Cardiovascular Research
Humus Inc
Vrije Universiteit Amsterdam
Solid Biosciences
Washington University St. Louis
University of Granada
University of Groningen
Ludwig Maximilian University of Munich
National Institutes of Health
James Cook University Queensland
University of Glasgow
University of Münster
University of California at San Diego
University of Cambridge
Leiden University
Pfizer
Jülich Research Centre
University of Trento
University of Freiburg
University of Toronto
University College London
Johnson & Johnson
University of Tartu
University of Liverpool
University of Iowa
University of Göttingen
Dalhousie University
Stanford University
23andMe Inc.
University of California at Los Angeles

Research output: Contribution to journal › Article › peer-review

1638 Citations (Scopus)

Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Original language	English
Pages (from-to)	431-444
Number of pages	14
Journal	Nature Genetics
Volume	51
Issue number	3
DOIs	https://doi.org/10.1038/s41588-019-0344-8
Publication status	Published - 25 Feb 2019
Externally published	Yes

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10.1038/s41588-019-0344-8

Cite this

@article{74fbe741c0614ab09ac8f6190b4cb41e,

title = "Identification of common genetic risk variants for autism spectrum disorder",

abstract = "Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1\% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.",

author = "\{Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium\} and BUPGEN and \{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium\} and \{23andMe Research Team\} and Jakob Grove and Stephan Ripke and Als, \{Thomas D.\} and Manuel Mattheisen and Walters, \{Raymond K.\} and Hyejung Won and Jonatan Pallesen and Esben Agerbo and Andreassen, \{Ole A.\} and Richard Anney and Swapnil Awashti and Rich Belliveau and Francesco Bettella and Buxbaum, \{Joseph D.\} and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Felecia Cerrato and Kimberly Chambert and Christensen, \{Jane H.\} and Claire Churchhouse and Karin Dellenvall and Ditte Demontis and \{De Rubeis\}, Silvia and Bernie Devlin and Srdjan Djurovic and Dumont, \{Ashley L.\} and Goldstein, \{Jacqueline I.\} and Hansen, \{Christine S.\} and Hauberg, \{Mads Engel\} and Hollegaard, \{Mads V.\} and Sigrun Hope and Howrigan, \{Daniel P.\} and Hailiang Huang and Hultman, \{Christina M.\} and Lambertus Klei and Julian Maller and Joanna Martin and Martin, \{Alicia R.\} and Moran, \{Jennifer L.\} and Mette Nyegaard and Terje N{\ae}rland and Palmer, \{Duncan S.\} and Aarno Palotie and Pedersen, \{Carsten B{\o}cker\} and Pedersen, \{Marianne Gi{\o}rtz\} and Timothy dPoterba and Poulsen, \{Jesper Buchhave\} and Pourcain, \{Beate St\} and Per Qvist and Hottenga, \{Jouke Jan\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = feb,

day = "25",

doi = "10.1038/s41588-019-0344-8",

language = "English",

volume = "51",

pages = "431--444",

journal = "Nature Genetics",

issn = "1061-4036",

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Identification of common genetic risk variants for autism spectrum disorder. / Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium; BUPGEN; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium et al.
In: Nature Genetics, Vol. 51, No. 3, 25.02.2019, p. 431-444.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Identification of common genetic risk variants for autism spectrum disorder

AU - Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium

AU - BUPGEN

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - 23andMe Research Team

AU - Grove, Jakob

AU - Ripke, Stephan

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AU - Devlin, Bernie

AU - Djurovic, Srdjan

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AU - Hollegaard, Mads V.

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AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - dPoterba, Timothy

AU - Poulsen, Jesper Buchhave

AU - Pourcain, Beate St

AU - Qvist, Per

AU - Hottenga, Jouke Jan

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AB - Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

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DO - 10.1038/s41588-019-0344-8

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SN - 1061-4036

VL - 51

SP - 431

EP - 444

JO - Nature Genetics

JF - Nature Genetics

IS - 3

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Identification of common genetic risk variants for autism spectrum disorder

Abstract

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