Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Ditte Demontis; Raymond K. Walters; Joanna Martin; Manuel Mattheisen; Thomas D. Als; Esben Agerbo; Gisli Baldursson; Rich Belliveau; Jonas Bybjerg-Grauholm; Marie Baekvad-Hansen; Felecia Cerrato; Kimberly Chambert; Claire Churchhouse; Ashley Dumont; Nicholas Eriksson; Michael Gandal; Jacqueline I. Goldstein; Katrina L. Grasby; Jakob Grove; Olafur O. Gudmundsson; Christine S. Hansen; Mads Engel Hauberg; Mads V. Hollegaard; Daniel P. Howrigan; Hailiang Huang; Julian B. Maller; Alicia R. Martin; Nicholas G. Martin; Jennifer Moran; Jonatan Pallesen; Duncan S. Palmer; Carsten Bocker Pedersen; Marianne Giortz Pedersen; Timothy Poterba; Jesper Buchhave Poulsen; Stephan Ripke; Elise B. Robinson; F. Kyle Satterstrom; Hreinn Stefansson; Christine Stevens; Patrick Turley; G. Bragi Walters; Hyejung Won; Margaret J. Wright; Ole A. Andreassen; Philip Asherson; Christie L. Burton; Dorret I. Boomsma; Bru Cormand; Soren Dalsgaard; Klaus-Peter Lesch; ADHD Working Group of the Psychiatric Genomics Consortium; Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; 23andMe Research team; Anders D. Børglum; Stephen V. Faraone; Benjamin M. Neale

doi:10.1038/s41588-018-0269-7

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Ditte Demontis, Raymond K. Walters, Joanna Martin, Manuel Mattheisen, Thomas D. Als, Esben Agerbo, Gisli Baldursson, Rich Belliveau, Jonas Bybjerg-Grauholm, Marie Baekvad-Hansen, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Ashley Dumont, Nicholas Eriksson, Michael Gandal, Jacqueline I. Goldstein, Katrina L. Grasby, Jakob Grove, Olafur O. GudmundssonChristine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian B. Maller, Alicia R. Martin, Nicholas G. Martin, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bocker Pedersen, Marianne Giortz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Elise B. Robinson, F. Kyle Satterstrom, Hreinn Stefansson, Christine Stevens, Patrick Turley, G. Bragi Walters, Hyejung Won, Margaret J. Wright, Ole A. Andreassen, Philip Asherson, Christie L. Burton, Dorret I. Boomsma, Bru Cormand, Soren Dalsgaard, Klaus-Peter Lesch, ADHD Working Group of the Psychiatric Genomics Consortium, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research team, Anders D. Børglum^*, Stephen V. Faraone^*, Benjamin M. Neale^*

^*Corresponding author for this work

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

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Original language	English
Pages (from-to)	63-75
Number of pages	16
Journal	Nature Genetics
Volume	51
Issue number	1
DOIs	https://doi.org/10.1038/s41588-018-0269-7
Publication status	Published - Jan 2019

Keywords

DEFICIT HYPERACTIVITY DISORDER
LD SCORE REGRESSION
ASSOCIATION METAANALYSIS
GENETIC ARCHITECTURE
PROVIDES INSIGHTS
MAJOR DEPRESSION
SEXUAL-BEHAVIOR
POLYGENIC RISK
IDENTIFIES 11
US CHILDREN

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Demontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G., Belliveau, R., Bybjerg-Grauholm, J., Baekvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., Goldstein, J. I., Grasby, K. L., Grove, J., ... Neale, B. M. (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics, 51(1), 63-75. https://doi.org/10.1038/s41588-018-0269-7

@article{e704b3af687247a48d305d3213f49eed,

title = "Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder",

abstract = "Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.",

keywords = "DEFICIT HYPERACTIVITY DISORDER, LD SCORE REGRESSION, ASSOCIATION METAANALYSIS, GENETIC ARCHITECTURE, PROVIDES INSIGHTS, MAJOR DEPRESSION, SEXUAL-BEHAVIOR, POLYGENIC RISK, IDENTIFIES 11, US CHILDREN",

author = "Ditte Demontis and Walters, {Raymond K.} and Joanna Martin and Manuel Mattheisen and Als, {Thomas D.} and Esben Agerbo and Gisli Baldursson and Rich Belliveau and Jonas Bybjerg-Grauholm and Marie Baekvad-Hansen and Felecia Cerrato and Kimberly Chambert and Claire Churchhouse and Ashley Dumont and Nicholas Eriksson and Michael Gandal and Goldstein, {Jacqueline I.} and Grasby, {Katrina L.} and Jakob Grove and Gudmundsson, {Olafur O.} and Hansen, {Christine S.} and Hauberg, {Mads Engel} and Hollegaard, {Mads V.} and Howrigan, {Daniel P.} and Hailiang Huang and Maller, {Julian B.} and Martin, {Alicia R.} and Martin, {Nicholas G.} and Jennifer Moran and Jonatan Pallesen and Palmer, {Duncan S.} and Pedersen, {Carsten Bocker} and Pedersen, {Marianne Giortz} and Timothy Poterba and Poulsen, {Jesper Buchhave} and Stephan Ripke and Robinson, {Elise B.} and Satterstrom, {F. Kyle} and Hreinn Stefansson and Christine Stevens and Patrick Turley and Walters, {G. Bragi} and Hyejung Won and Wright, {Margaret J.} and Andreassen, {Ole A.} and Philip Asherson and Burton, {Christie L.} and Boomsma, {Dorret I.} and Bru Cormand and Soren Dalsgaard and Klaus-Peter Lesch and {ADHD Working Group of the Psychiatric Genomics Consortium} and {Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium} and {23andMe Research team} and B{\o}rglum, {Anders D.} and Faraone, {Stephen V.} and Neale, {Benjamin M.}",

note = "Funding Information: A.T. received ADHD funding from the Wellcome Trust, Medical Research Council (MRC UK), Action Medical Research. Funding Information: We thank the customers of 23andMe who answered surveys, as well as the employees of 23andMe who together made this research possible. The QIMR studies were supported by funding from the Australian National Health and Medical Research Council (grant numbers: 241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496739, 552485, and 552498, and, most recently, 1049894) and the Australian Research Council (grant numbers: A7960034, A79906588, A79801419, DP0212016, and DP0343921). SEM is supported by an NHMRC fellowship (1103623). Additional acknowledgements can be found in the Supplementary Note. Funding Information: B.F.{\textquoteright}s research is supported by funding from a personal Vici grant of the Netherlands Organisation for Scientific Research (NWO; grant 016-130-669, to B.F.), the EC{\textquoteright}s Seventh Framework Programme (grant 602805 (Aggressotype), 602450 (IMAGEMEND), and 278948 (TACTICS)), and from the EC{\textquoteright}s Horizon 2020 Programme (grant643051 (MiND) and 667302 (CoCA)). Additionally, this work was supported by the European College of Neuropsychopharmacology (ECNP Network {\textquoteleft}ADHD across the Lifespan{\textquoteright}). Funding Information: We thank T. Lehner, A. Addington and G. Senthil for their support in the Psychiatric Genomics Consortium. S.V.F. is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Norway, the EC{\textquoteright}s Seventh Framework Programme (grant 602805), the EC{\textquoteright}s Horizon 2020 (grant 667302) and NIMH grants 5R01MH101519 and U01 MH109536-01. J.M. was supported by the Wellcome Trust (grant 106047). Funding Information: L.A.R. has received honoraria, has been on the speakers{\textquoteright} bureau/advisory board and/or has acted as a consultant for Eli-Lilly, Janssen-Cilag, Novartis, Medice and Shire in the past three years. He receives authorship royalties from Oxford Press and ArtMed. He also received a travel award from Shire for taking part in the 2015 WFADHD meeting. The ADHD and Juvenile Bipolar Disorder Outpatient Programs unrestricted educational and research support from the following pharmaceutical companies in the past three years: Eli-Lilly, Janssen-Cilag, Novartis and Shire. Over the past three years E.J.S.-B. has received speaker fees, consultancy, research funding and conference support from Shire Pharma and speaker fees from Janssen-Cilag. He has received consultancy fees from Neurotech solutions, Aarhus University, Copenhagen University and Berhanderling, Skolerne, Copenhagen, KU Leuven and book royalties from OUP and Jessica Kingsley. He is the editor-in-chief of the Journal of Child Psychology and Psychiatry, for which his university receives financial support. B.F. has received educational speaking fees from Merz and Shire. Funding Information: J.H. is supported by grants from Stiftelsen K.G. Jebsen, University of Bergen and The Research Council of Norway. B.C. received financial support for this research from the Spanish {\textquoteleft}Ministerio de Econom{\'i}a y Competitividad{\textquoteright} (SAF2015-68341-R) and {\textquoteleft}Generalitat de Catalunya/ AGAUR{\textquoteright} (2017-SGR-738). B.B., A.R. and collaborators received funding from the EC{\textquoteright}s Seventh Framework Programme (grant 602805, Aggressotype), the EC{\textquoteright}s H2020 Programme (grants 667302, CoCA, and 402003, MiND), the ECNP network {\textquoteleft}ADHD across the lifespan{\textquoteright} and DFG CRC 1193, subproject Z03. O.A.A. is supported by the Research Council of Norway (grants: 223273, 248778, 213694, 249711), and KG Jebsen Stiftelsen. Funding Information: The iPSYCH team acknowledges funding from the Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project 294838), the European Community (EC) Horizon 2020 Programme (grant 667302 (CoCA)), from EC Seventh Framework Programme (grant 602805 (Aggressotype)), the Novo Nordisk Foundation for supporting the Danish National Biobank resource and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. The Broad Institute and Massachusetts General Hospital investigators would like to acknowledge support from the Stanley Medical Research Institute and NIH grants: 5U01MH094432-04(PI: Daly), 1R01MH094469 (PI: Neale), 1R01MH107649-01 (PI: Neale), 1R01MH109539-01 (PI: Daly). Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jan,

doi = "10.1038/s41588-018-0269-7",

language = "English",

volume = "51",

pages = "63--75",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

}

Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Cerrato, F, Chambert, K, Churchhouse, C, Dumont, A, Eriksson, N, Gandal, M, Goldstein, JI, Grasby, KL, Grove, J, Gudmundsson, OO, Hansen, CS, Hauberg, ME, Hollegaard, MV, Howrigan, DP, Huang, H, Maller, JB, Martin, AR, Martin, NG, Moran, J, Pallesen, J, Palmer, DS, Pedersen, CB, Pedersen, MG, Poterba, T, Poulsen, JB, Ripke, S, Robinson, EB, Satterstrom, FK, Stefansson, H, Stevens, C, Turley, P, Walters, GB, Won, H, Wright, MJ, Andreassen, OA, Asherson, P, Burton, CL, Boomsma, DI, Cormand, B, Dalsgaard, S, Lesch, K-P, ADHD Working Group of the Psychiatric Genomics Consortium, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research team, Børglum, AD, Faraone, SV & Neale, BM 2019, 'Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder', Nature Genetics, vol. 51, no. 1, pp. 63-75. https://doi.org/10.1038/s41588-018-0269-7

TY - JOUR

T1 - Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

AU - Demontis, Ditte

AU - Walters, Raymond K.

AU - Martin, Joanna

AU - Mattheisen, Manuel

AU - Als, Thomas D.

AU - Agerbo, Esben

AU - Baldursson, Gisli

AU - Belliveau, Rich

AU - Bybjerg-Grauholm, Jonas

AU - Baekvad-Hansen, Marie

AU - Cerrato, Felecia

AU - Chambert, Kimberly

AU - Churchhouse, Claire

AU - Dumont, Ashley

AU - Eriksson, Nicholas

AU - Gandal, Michael

AU - Goldstein, Jacqueline I.

AU - Grasby, Katrina L.

AU - Grove, Jakob

AU - Gudmundsson, Olafur O.

AU - Hansen, Christine S.

AU - Hauberg, Mads Engel

AU - Hollegaard, Mads V.

AU - Howrigan, Daniel P.

AU - Huang, Hailiang

AU - Maller, Julian B.

AU - Martin, Alicia R.

AU - Martin, Nicholas G.

AU - Moran, Jennifer

AU - Pallesen, Jonatan

AU - Palmer, Duncan S.

AU - Pedersen, Carsten Bocker

AU - Pedersen, Marianne Giortz

AU - Poterba, Timothy

AU - Poulsen, Jesper Buchhave

AU - Ripke, Stephan

AU - Robinson, Elise B.

AU - Satterstrom, F. Kyle

AU - Stefansson, Hreinn

AU - Stevens, Christine

AU - Turley, Patrick

AU - Walters, G. Bragi

AU - Won, Hyejung

AU - Wright, Margaret J.

AU - Andreassen, Ole A.

AU - Asherson, Philip

AU - Burton, Christie L.

AU - Boomsma, Dorret I.

AU - Cormand, Bru

AU - Dalsgaard, Soren

AU - Lesch, Klaus-Peter

AU - ADHD Working Group of the Psychiatric Genomics Consortium

AU - Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

AU - 23andMe Research team

AU - Børglum, Anders D.

AU - Faraone, Stephen V.

AU - Neale, Benjamin M.

N1 - Funding Information: A.T. received ADHD funding from the Wellcome Trust, Medical Research Council (MRC UK), Action Medical Research. Funding Information: We thank the customers of 23andMe who answered surveys, as well as the employees of 23andMe who together made this research possible. The QIMR studies were supported by funding from the Australian National Health and Medical Research Council (grant numbers: 241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496739, 552485, and 552498, and, most recently, 1049894) and the Australian Research Council (grant numbers: A7960034, A79906588, A79801419, DP0212016, and DP0343921). SEM is supported by an NHMRC fellowship (1103623). Additional acknowledgements can be found in the Supplementary Note. Funding Information: B.F.’s research is supported by funding from a personal Vici grant of the Netherlands Organisation for Scientific Research (NWO; grant 016-130-669, to B.F.), the EC’s Seventh Framework Programme (grant 602805 (Aggressotype), 602450 (IMAGEMEND), and 278948 (TACTICS)), and from the EC’s Horizon 2020 Programme (grant643051 (MiND) and 667302 (CoCA)). Additionally, this work was supported by the European College of Neuropsychopharmacology (ECNP Network ‘ADHD across the Lifespan’). Funding Information: We thank T. Lehner, A. Addington and G. Senthil for their support in the Psychiatric Genomics Consortium. S.V.F. is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Norway, the EC’s Seventh Framework Programme (grant 602805), the EC’s Horizon 2020 (grant 667302) and NIMH grants 5R01MH101519 and U01 MH109536-01. J.M. was supported by the Wellcome Trust (grant 106047). Funding Information: L.A.R. has received honoraria, has been on the speakers’ bureau/advisory board and/or has acted as a consultant for Eli-Lilly, Janssen-Cilag, Novartis, Medice and Shire in the past three years. He receives authorship royalties from Oxford Press and ArtMed. He also received a travel award from Shire for taking part in the 2015 WFADHD meeting. The ADHD and Juvenile Bipolar Disorder Outpatient Programs unrestricted educational and research support from the following pharmaceutical companies in the past three years: Eli-Lilly, Janssen-Cilag, Novartis and Shire. Over the past three years E.J.S.-B. has received speaker fees, consultancy, research funding and conference support from Shire Pharma and speaker fees from Janssen-Cilag. He has received consultancy fees from Neurotech solutions, Aarhus University, Copenhagen University and Berhanderling, Skolerne, Copenhagen, KU Leuven and book royalties from OUP and Jessica Kingsley. He is the editor-in-chief of the Journal of Child Psychology and Psychiatry, for which his university receives financial support. B.F. has received educational speaking fees from Merz and Shire. Funding Information: J.H. is supported by grants from Stiftelsen K.G. Jebsen, University of Bergen and The Research Council of Norway. B.C. received financial support for this research from the Spanish ‘Ministerio de Economía y Competitividad’ (SAF2015-68341-R) and ‘Generalitat de Catalunya/ AGAUR’ (2017-SGR-738). B.B., A.R. and collaborators received funding from the EC’s Seventh Framework Programme (grant 602805, Aggressotype), the EC’s H2020 Programme (grants 667302, CoCA, and 402003, MiND), the ECNP network ‘ADHD across the lifespan’ and DFG CRC 1193, subproject Z03. O.A.A. is supported by the Research Council of Norway (grants: 223273, 248778, 213694, 249711), and KG Jebsen Stiftelsen. Funding Information: The iPSYCH team acknowledges funding from the Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project 294838), the European Community (EC) Horizon 2020 Programme (grant 667302 (CoCA)), from EC Seventh Framework Programme (grant 602805 (Aggressotype)), the Novo Nordisk Foundation for supporting the Danish National Biobank resource and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. The Broad Institute and Massachusetts General Hospital investigators would like to acknowledge support from the Stanley Medical Research Institute and NIH grants: 5U01MH094432-04(PI: Daly), 1R01MH094469 (PI: Neale), 1R01MH107649-01 (PI: Neale), 1R01MH109539-01 (PI: Daly). Publisher Copyright: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/1

Y1 - 2019/1

N2 - Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

AB - Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

KW - DEFICIT HYPERACTIVITY DISORDER

KW - LD SCORE REGRESSION

KW - ASSOCIATION METAANALYSIS

KW - GENETIC ARCHITECTURE

KW - PROVIDES INSIGHTS

KW - MAJOR DEPRESSION

KW - SEXUAL-BEHAVIOR

KW - POLYGENIC RISK

KW - IDENTIFIES 11

KW - US CHILDREN

U2 - 10.1038/s41588-018-0269-7

DO - 10.1038/s41588-018-0269-7

M3 - Article

SN - 1061-4036

VL - 51

SP - 63

EP - 75

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -