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

23andMe Research Team, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

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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 languageEnglish
Pages (from-to)63-75
Number of pages13
JournalNature Genetics
Volume51
Issue number1
Early online date26 Nov 2018
DOIs
Publication statusPublished - Jan 2019

Bibliographical 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.’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.

Funding

A.T. received ADHD funding from the Wellcome Trust, Medical Research Council (MRC UK), Action Medical Research. 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. 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’). 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). 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. 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. 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).

FundersFunder number
CIRRAU Center
EC’s H2020 Programme
EC’s Horizon 2020
EC’s Horizon 2020 Programme
K.G. Jebsen Centre for Research
MRC UK
Mind
Shire Pharma
National Institutes of Health1R01MH094469, 1R01MH107649-01, 1R01MH109539-01, 5U01MH094432-04
National Institute of Mental HealthU01 MH109536-01, R00MH113823, 5R01MH101519
Massachusetts General Hospital
Stanley Medical Research Institute
Wellcome Trust106047
Horizon 2020 Framework Programme667302, 294838
Chiropractic and Osteopathic College of Australasia402003
University Hospitals
Broad Institute
Cilag
Medical Research Council
Action Medical Research
European Commission
European Research Council
Australian Research CouncilA7960034, DP0212016, A79801419, DP0343921, A79906588
National Health and Medical Research Council339462, 389892, 389891, 241944, 552485, 442981, 443036, 552498, 496739, 389875, 442915, 389927, 389938, 1049894, 1103623
Deutsche Forschungsgemeinschaft213694, 223273, 249711, CRC 1193, 248778
Generalitat de Catalunya
Agència de Gestió d'Ajuts Universitaris i de Recerca2017-SGR-738
Nederlandse Organisatie voor Wetenschappelijk Onderzoek016-130-669
Ministerio de Economía y CompetitividadSAF2015-68341-R
LundbeckfondenR155-2014-1724, R102-A9118
Seventh Framework Programme602805, 602450, 278948
Universitetet i Bergen
Norges forskningsråd
European College of Neuropsychopharmacology
Novo Nordisk Fonden

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