Identification of common genetic risk variants for autism spectrum disorder

Jakob Grove, Stephan Ripke, Thomas D. Als, Manuel Mattheisen, Raymond K. Walters, Hyejung Won, Jonatan Pallesen, Esben Agerbo, Ole A. Andreassen, Richard Anney, Swapnil Awashti, Rich Belliveau, Francesco Bettella, Joseph D. Buxbaum, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Felecia Cerrato, Kimberly Chambert, Jane H. Christensen, Claire Churchhouse & 33 others Karin Dellenvall, Ditte Demontis, Silvia de Rubeis, Bernie Devlin, Srdjan Djurovic, Ashley L. Dumont, Jacqueline I. Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Aartjan T. F. Beekman, Rick Jansen, Christel M. Middeldorp, Yuri Milaneschi, Wouter J. Peyrot, Danielle Posthuma, Robert Schoevers, Johannes H. Smit, E. J. C. de Geus, Johannes H. Smit, E. J. C. de Geus, Brenda W. J. H. Penninx, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, Kari Stefansson, Daniel H. Geschwind, Merete Nordentoft, David M. Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Benjamin M. Neale, Mark J. Daly, A. D. Børglum

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 - 1 Mar 2019

Cite this

Grove, J., Ripke, S., Als, T. D., Mattheisen, M., Walters, R. K., Won, H., ... Børglum, A. D. (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
Grove, Jakob ; Ripke, Stephan ; Als, Thomas D. ; Mattheisen, Manuel ; Walters, Raymond K. ; Won, Hyejung ; Pallesen, Jonatan ; Agerbo, Esben ; Andreassen, Ole A. ; Anney, Richard ; Awashti, Swapnil ; Belliveau, Rich ; Bettella, Francesco ; Buxbaum, Joseph D. ; Bybjerg-Grauholm, Jonas ; Bækvad-Hansen, Marie ; Cerrato, Felecia ; Chambert, Kimberly ; Christensen, Jane H. ; Churchhouse, Claire ; Dellenvall, Karin ; Demontis, Ditte ; de Rubeis, Silvia ; Devlin, Bernie ; Djurovic, Srdjan ; Dumont, Ashley L. ; Goldstein, Jacqueline I. ; Hansen, Christine S. ; Hauberg, Mads Engel ; Hollegaard, Mads V. ; Beekman, Aartjan T. F. ; Jansen, Rick ; Middeldorp, Christel M. ; Milaneschi, Yuri ; Peyrot, Wouter J. ; Posthuma, Danielle ; Schoevers, Robert ; Smit, Johannes H. ; de Geus, E. J. C. ; Smit, Johannes H. ; de Geus, E. J. C. ; Penninx, Brenda W. J. H. ; Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium ; Stefansson, Kari ; Geschwind, Daniel H. ; Nordentoft, Merete ; Hougaard, David M. ; Werge, Thomas ; Mors, Ole ; Bo Mortensen, Preben ; Neale, Benjamin M. ; Daly, Mark J. ; Børglum, A. D. / 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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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 = "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 Beekman, {Aartjan T. F.} and Rick Jansen and Middeldorp, {Christel M.} and Yuri Milaneschi and Peyrot, {Wouter J.} and Danielle Posthuma and Robert Schoevers and Smit, {Johannes H.} and {de Geus}, {E. J. C.} and Smit, {Johannes H.} and {de Geus}, {E. J. C.} and Penninx, {Brenda W. J. H.} and {Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium} and Kari Stefansson and Geschwind, {Daniel H.} and Merete Nordentoft and Hougaard, {David M.} and Thomas Werge and Ole Mors and {Bo Mortensen}, Preben and Neale, {Benjamin M.} and Daly, {Mark J.} and B{\o}rglum, {A. D.}",
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Grove, J, Ripke, S, Als, TD, Mattheisen, M, Walters, RK, Won, H, Pallesen, J, Agerbo, E, Andreassen, OA, Anney, R, Awashti, S, Belliveau, R, Bettella, F, Buxbaum, JD, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, JH, Churchhouse, C, Dellenvall, K, Demontis, D, de Rubeis, S, Devlin, B, Djurovic, S, Dumont, AL, Goldstein, JI, Hansen, CS, Hauberg, ME, Hollegaard, MV, Beekman, ATF, Jansen, R, Middeldorp, CM, Milaneschi, Y, Peyrot, WJ, Posthuma, D, Schoevers, R, Smit, JH, de Geus, EJC, Smit, JH, de Geus, EJC, Penninx, BWJH, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, Stefansson, K, Geschwind, DH, Nordentoft, M, Hougaard, DM, Werge, T, Mors, O, Bo Mortensen, P, Neale, BM, Daly, MJ & Børglum, AD 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. / Grove, Jakob; Ripke, Stephan; Als, Thomas D.; Mattheisen, Manuel; Walters, Raymond K.; Won, Hyejung; Pallesen, Jonatan; Agerbo, Esben; Andreassen, Ole A.; Anney, Richard; Awashti, Swapnil; Belliveau, Rich; Bettella, Francesco; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Christensen, Jane H.; Churchhouse, Claire; Dellenvall, Karin; Demontis, Ditte; de Rubeis, Silvia; Devlin, Bernie; Djurovic, Srdjan; Dumont, Ashley L.; Goldstein, Jacqueline I.; Hansen, Christine S.; Hauberg, Mads Engel; Hollegaard, Mads V.; Beekman, Aartjan T. F.; Jansen, Rick; Middeldorp, Christel M.; Milaneschi, Yuri; Peyrot, Wouter J.; Posthuma, Danielle; Schoevers, Robert; Smit, Johannes H.; de Geus, E. J. C.; Smit, Johannes H.; de Geus, E. J. C.; Penninx, Brenda W. J. H.; Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium; Stefansson, Kari; Geschwind, Daniel H.; Nordentoft, Merete; Hougaard, David M.; Werge, Thomas; Mors, Ole; Bo Mortensen, Preben; Neale, Benjamin M.; Daly, Mark J.; Børglum, A. D.

In: Nature Genetics, Vol. 51, No. 3, 01.03.2019, 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 - Beekman, Aartjan T. F.

AU - Jansen, Rick

AU - Middeldorp, Christel M.

AU - Milaneschi, Yuri

AU - Peyrot, Wouter J.

AU - Posthuma, Danielle

AU - Schoevers, Robert

AU - Smit, Johannes H.

AU - de Geus, E. J. C.

AU - Smit, Johannes H.

AU - de Geus, E. J. C.

AU - Penninx, Brenda W. J. H.

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

AU - Stefansson, Kari

AU - Geschwind, Daniel H.

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Werge, Thomas

AU - Mors, Ole

AU - Bo Mortensen, Preben

AU - Neale, Benjamin M.

AU - Daly, Mark J.

AU - Børglum, A. D.

PY - 2019/3/1

Y1 - 2019/3/1

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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EP - 444

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Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H et al. Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics. 2019 Mar 1;51(3):431-444. https://doi.org/10.1038/s41588-019-0344-8