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

the 23 and Me Research Team; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; Ditte Demontis; Raymond K. Walters; Joanna Martin; Manuel Mattheisen; Thomas D. Als; Esben Agerbo; Gísli Baldursson; Rich Belliveau; Jonas Bybjerg-Grauholm; Marie Bækvad-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 Bøcker Pedersen; Marianne Giørtz Pedersen; Timothy Poterba; Jesper Buchhave Poulsen; Stephan Ripke; Elise B. Robinson; F. Kyle Satterstrom; George Davey Smith; Gareth E. Davies; David M. Evans; John P. Kemp; Susan Ring; Evie Stergiakouli; Beate St Pourcain; Camilla Stoltenberg; Nicholas J. Timpson; Kate Langley; Anita Thapar; Sarah E. Medland

doi:10.1038/s41588-018-0269-7

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

the 23 and Me Research Team, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Ditte Demontis, Raymond K. Walters, Joanna Martin, Manuel Mattheisen, Thomas D. Als, Esben Agerbo, Gísli Baldursson, Rich Belliveau, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Ashley Dumont, Nicholas Eriksson, Michael Gandal, Jacqueline I. GoldsteinKatrina 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 Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Elise B. Robinson, F. Kyle Satterstrom, George Davey Smith, Gareth E. Davies, David M. Evans, John P. Kemp, Susan Ring, Evie Stergiakouli, Beate St Pourcain, Camilla Stoltenberg, Nicholas J. Timpson, Kate Langley, Anita Thapar, Sarah E. Medland

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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 language	English
Pages (from-to)	63-75
Number of pages	13
Journal	Nature Genetics
Volume	51
Issue number	1
Early online date	26 Nov 2018
DOIs	https://doi.org/10.1038/s41588-018-0269-7
Publication status	Published - 1 Jan 2019

Keywords

Adolescent
Attention Deficit Disorder with Hyperactivity/genetics
Brain/physiology
Child
Child, Preschool
Cohort Studies
Female
Gene Expression Regulation/genetics
Genetic Loci/genetics
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study/methods
Humans
Male
Polymorphism, Single Nucleotide/genetics
Risk

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the 23 and Me Research Team, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Demontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G., Belliveau, R., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., ... Medland, S. E. (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

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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 = "Adolescent, Attention Deficit Disorder with Hyperactivity/genetics, Brain/physiology, Child, Child, Preschool, Cohort Studies, Female, Gene Expression Regulation/genetics, Genetic Loci/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Humans, Male, Polymorphism, Single Nucleotide/genetics, Risk",

author = "{the 23 and Me Research Team} and {ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and {Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium} and Ditte Demontis and Walters, {Raymond K.} and Joanna Martin and Manuel Mattheisen and Als, {Thomas D.} and Esben Agerbo and G{\'i}sli Baldursson and Rich Belliveau and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-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 B{\o}cker} and Pedersen, {Marianne Gi{\o}rtz} and Timothy Poterba and Poulsen, {Jesper Buchhave} and Stephan Ripke and Robinson, {Elise B.} and Satterstrom, {F. Kyle} and Smith, {George Davey} and Davies, {Gareth E.} and Evans, {David M.} and Kemp, {John P.} and Susan Ring and Evie Stergiakouli and Pourcain, {Beate St} and Camilla Stoltenberg and Timpson, {Nicholas J.} and Kate Langley and Anita Thapar and Medland, {Sarah E.}",

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the 23 and Me Research Team, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Bækvad-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, Smith, GD, Davies, GE, Evans, DM, Kemp, JP, Ring, S , Stergiakouli, E , Pourcain, BS, Stoltenberg, C, Timpson, NJ, Langley, K, Thapar, A & Medland, SE 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

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. / the 23 and Me Research Team; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium et al.
In: Nature Genetics, Vol. 51, No. 1, 01.01.2019, p. 63-75.

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

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AU - the 23 and Me Research Team

AU - ADHD Working Group of the Psychiatric Genomics Consortium (PGC)

AU - Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

AU - Demontis, Ditte

AU - Walters, Raymond K.

AU - Martin, Joanna

AU - Mattheisen, Manuel

AU - Als, Thomas D.

AU - Agerbo, Esben

AU - Baldursson, Gísli

AU - Belliveau, Rich

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-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.

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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 Bøcker

AU - Pedersen, Marianne Giørtz

AU - Poterba, Timothy

AU - Poulsen, Jesper Buchhave

AU - Ripke, Stephan

AU - Robinson, Elise B.

AU - Satterstrom, F. Kyle

AU - Smith, George Davey

AU - Davies, Gareth E.

AU - Evans, David M.

AU - Kemp, John P.

AU - Ring, Susan

AU - Stergiakouli, Evie

AU - Pourcain, Beate St

AU - Stoltenberg, Camilla

AU - Timpson, Nicholas J.

AU - Langley, Kate

AU - Thapar, Anita

AU - Medland, Sarah E.

PY - 2019/1/1

Y1 - 2019/1/1

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.

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KW - Brain/physiology

KW - Child

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KW - Cohort Studies

KW - Female

KW - Gene Expression Regulation/genetics

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide/genetics

KW - Risk

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the 23 and Me Research Team, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Demontis D, Walters RK, Martin J et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics. 2019 Jan 1;51(1):63-75. Epub 2018 Nov 26. doi: 10.1038/s41588-018-0269-7

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

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

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Keywords

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Professor George Davey Smith

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