Identification of common genetic risk variants for autism spectrum disorder

Jakob Grove; Abdel Abdellaoui; Eske M. Derks; Conor V. Dolan; Jouke Jan Hottenga; Rick Jansen; Hamdi Mbarek; Christel M. Middeldorp; Yuri Milaneschi; Michel G. Nivard; Danielle Posthuma; Gonneke Willemsen; Dorret I. Boomsma; E. J.C. de Geus; Brenda W.J.H. Penninx; Anders D. Børglum; 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

Jakob Grove, Abdel Abdellaoui, Eske M. Derks, Conor V. Dolan, Jouke Jan Hottenga, Rick Jansen, Hamdi Mbarek, Christel M. Middeldorp, Yuri Milaneschi, Michel G. Nivard, Danielle Posthuma, Gonneke Willemsen, Dorret I. Boomsma, E. J.C. de Geus, Brenda W.J.H. Penninx, Anders D. Børglum^*, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23Andme Research Team

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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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 - Mar 2019

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Identification of common genetic risk variants for autism spectrum disorderFinal published version, 2.91 MBLicence: Article 25fa Dutch Copyright Act

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Grove, J., Abdellaoui, A., Derks, E. M., Dolan, C. V., Hottenga, J. J., Jansen, R., Mbarek, H., Middeldorp, C. M., Milaneschi, Y., Nivard, M. G., Posthuma, D., Willemsen, G., Boomsma, D. I., de Geus, E. J. C., Penninx, B. W. J. H., Børglum, A. D., 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

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year = "2019",

month = mar,

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

language = "English",

volume = "51",

pages = "431--444",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

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Grove, J, Abdellaoui, A, Derks, EM, Dolan, CV , Hottenga, JJ, Jansen, R, Mbarek, H, Middeldorp, CM, Milaneschi, Y, Nivard, MG , Posthuma, D , Willemsen, G , Boomsma, DI , de Geus, EJC, Penninx, BWJH, Børglum, AD, 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

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AU - Als, Thomas D.

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AU - Walters, Raymond K.

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AU - Pallesen, Jonatan

AU - Agerbo, Esben

AU - Andreassen, Ole A.

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AU - Walters, G. Bragi

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AU - Smith, Daniel J.

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AU - Strohmaier, Jana

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AU - Treutlein, Jens

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AU - Uitterlinden, André G.

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AU - van Hemert, Albert M.

AU - Viktorin, Alexander

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

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AU - Mountain, Joanna L.

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AU - Northover, Carrie A.M.

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Y1 - 2019/3

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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UR - http://www.scopus.com/inward/citedby.url?scp=85062110842&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0344-8

DO - 10.1038/s41588-019-0344-8

M3 - Article

AN - SCOPUS:85062110842

VL - 51

SP - 431

EP - 444

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -

Identification of common genetic risk variants for autism spectrum disorder

Abstract

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UN SDGs

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