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

Research output: Contribution to JournalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)431-444
Number of pages14
JournalNature Genetics
Volume51
Issue number3
DOIs
Publication statusPublished - Mar 2019

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Genome-Wide Association Study
Phenotype
Sample Size
Meta-Analysis
Autism Spectrum Disorder
Schizophrenia
Genome
Depression
Population

Cite this

Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, & 23Andme Research Team (2019). Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics, 51(3), 431-444. https://doi.org/10.1038/s41588-019-0344-8
Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium ; BUPGEN ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium ; 23Andme Research Team. / Identification of common genetic risk variants for autism spectrum disorder. In: Nature Genetics. 2019 ; Vol. 51, No. 3. pp. 431-444.
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Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium & 23Andme Research Team 2019, 'Identification of common genetic risk variants for autism spectrum disorder' Nature Genetics, vol. 51, no. 3, pp. 431-444. https://doi.org/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.

In: Nature Genetics, Vol. 51, No. 3, 03.2019, p. 431-444.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

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

AU - Grove, Jakob

AU - Ripke, Stephan

AU - Als, Thomas D.

AU - Mattheisen, Manuel

AU - Walters, Raymond K.

AU - Won, Hyejung

AU - Pallesen, Jonatan

AU - Agerbo, Esben

AU - Andreassen, Ole A.

AU - Anney, Richard

AU - Awashti, Swapnil

AU - Belliveau, Rich

AU - Bettella, Francesco

AU - Buxbaum, Joseph D.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Cerrato, Felecia

AU - Chambert, Kimberly

AU - Christensen, Jane H.

AU - Churchhouse, Claire

AU - Dellenvall, Karin

AU - Demontis, Ditte

AU - De Rubeis, Silvia

AU - Devlin, Bernie

AU - Djurovic, Srdjan

AU - Dumont, Ashley L.

AU - Goldstein, Jacqueline I.

AU - Hansen, Christine S.

AU - Hauberg, Mads Engel

AU - Hollegaard, Mads V.

AU - Hope, Sigrun

AU - Howrigan, Daniel P.

AU - Huang, Hailiang

AU - Hultman, Christina M.

AU - Klei, Lambertus

AU - Maller, Julian

AU - Martin, Joanna

AU - Martin, Alicia R.

AU - Moran, Jennifer L.

AU - Nyegaard, Mette

AU - Nærland, Terje

AU - Palmer, Duncan S.

AU - Palotie, Aarno

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - dPoterba, Timothy

AU - Poulsen, Jesper Buchhave

AU - Pourcain, Beate St

AU - Qvist, Per

AU - Rehnström, Karola

AU - Reichenberg, Abraham

AU - Reichert, Jennifer

AU - Robinson, Elise B.

AU - Roeder, Kathryn

AU - Roussos, Panos

AU - Saemundsen, Evald

AU - Sandin, Sven

AU - Satterstrom, F. Kyle

AU - Davey Smith, George

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Stevens, Christine R.

AU - Sullivan, Patrick F.

AU - Turley, Patrick

AU - Walters, G. Bragi

AU - Xu, Xinyi

AU - Wray, Naomi R.

AU - Trzaskowski, Maciej

AU - Byrne, Enda M.

AU - Abdellaoui, Abdel

AU - Adams, Mark J.

AU - Air, Tracy M.

AU - Andlauer, Till F.M.

AU - Bacanu, Silviu Alin

AU - Beekman, Aartjan T.F.

AU - Bigdeli, Tim B.

AU - Binder, Elisabeth B.

AU - Blackwood, Douglas H.R.

AU - Bryois, Julien

AU - Buttenschøn, Henriette N.

AU - Cai, Na

AU - Castelao, Enrique

AU - Clarke, Toni Kim

AU - Coleman, Jonathan R.I.

AU - Colodro-Conde, Lucía

AU - Couvy-Duchesne, Baptiste

AU - Craddock, Nick

AU - Crawford, Gregory E.

AU - Davies, Gail

AU - Deary, Ian J.

AU - Degenhardt, Franziska

AU - Derks, Eske M.

AU - Direk, Nese

AU - Dolan, Conor V.

AU - Dunn, Erin C.

AU - Eley, Thalia C.

AU - Escott-Price, Valentina

AU - Kiadeh, Farnush Farhadi Hassan

AU - Finucane, Hilary K.

AU - Forstner, Andreas J.

AU - Frank, Josef

AU - Gaspar, Héléna A.

AU - Gill, Michael

AU - Goes, Fernando S.

AU - Gordon, Scott D.

AU - Hall, Lynsey S.

AU - Hansen, Thomas F.

AU - Herms, Stefan

AU - Hickie, Ian B.

AU - Hoffmann, Per

AU - Homuth, Georg

AU - Horn, Carsten

AU - Hottenga, Jouke Jan

AU - Ising, Marcus

AU - Jansen, Rick

AU - Jorgenson, Eric

AU - Knowles, James A.

AU - Kohane, Isaac S.

AU - Kraft, Julia

AU - Kretzschmar, Warren W.

AU - Krogh, Jesper

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AU - Lind, Penelope A.

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AU - Maier, Wolfgang

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AU - Teumer, Alexander

AU - Thompson, Wesley

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AU - Thorgeirsson, Thorgeir E.

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AU - van Hemert, Albert M.

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AU - Visscher, Peter M.

AU - Wang, Yunpeng

AU - Webb, Bradley T.

AU - Weinsheimer, Shantel Marie

AU - Wellmann, Jürgen

AU - Willemsen, Gonneke

AU - Witt, Stephanie H.

AU - Wu, Yang

AU - Xi, Hualin S.

AU - Yang, Jian

AU - Zhang, Futao

AU - Arolt, Volker

AU - Baune, Bernhard T.

AU - Berger, Klaus

AU - Boomsma, Dorret I.

AU - Cichon, Sven

AU - Dannlowski, Udo

AU - de Geus, E. J.C.

AU - DePaulo, J. Raymond

AU - Domenici, Enrico

AU - Domschke, Katharina

AU - Esko, Tõnu

AU - Grabe, Hans J.

AU - Hamilton, Steven P.

AU - Hayward, Caroline

AU - Heath, Andrew C.

AU - Kendler, Kenneth S.

AU - Kloiber, Stefan

AU - Lewis, Glyn

AU - Li, Qingqin S.

AU - Lucae, Susanne

AU - Madden, Pamela A.F.

AU - Magnusson, Patrik K.

AU - Martin, Nicholas G.

AU - McIntosh, Andrew M.

AU - Metspalu, Andres

AU - Müller-Myhsok, Bertram

AU - Nöthen, Markus M.

AU - O’Donovan, Michael C.

AU - Paciga, Sara A.

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.J.H.

AU - Perlis, Roy H.

AU - Porteous, David J.

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AU - Preisig, Martin

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AU - Schaefer, Catherine

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AU - Smoller, Jordan W.

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AU - Uher, Rudolf

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AU - Weissman, Myrna M.

AU - Lewis, Cathryn M.

AU - Levinson, Douglas F.

AU - Breen, Gerome

AU - Agee, Michelle

AU - Alipanahi, Babak

AU - Auton, Adam

AU - Bell, Robert K.

AU - Bryc, Katarzyna

AU - Elson, Sarah L.

AU - Fontanillas, Pierre

AU - Furlotte, Nicholas A.

AU - Hromatka, Bethann S.

AU - Huber, Karen E.

AU - Kleinman, Aaron

AU - Litterman, Nadia K.

AU - McIntyre, Matthew H.

AU - Mountain, Joanna L.

AU - Noblin, Elizabeth S.

AU - Northover, Carrie A.M.

AU - Pitts, Steven J.

AU - Sathirapongsasuti, J. Fah

AU - Sazonova, Olga V.

AU - Shelton, Janie F.

AU - Shringarpure, Suyash

AU - Tung, Joyce Y.

AU - Vacic, Vladimir

AU - Wilson, Catherine H.

AU - Stefansson, Kari

AU - Geschwind, Daniel H.

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Werge, Thomas

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Neale, Benjamin M.

AU - Daly, Mark J.

AU - Børglum, Anders D.

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

PY - 2019/3

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N2 - 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.

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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JF - Nature Genetics

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Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23Andme Research Team. Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics. 2019 Mar;51(3):431-444. https://doi.org/10.1038/s41588-019-0344-8