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; 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; 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; Søren Dalsgaard; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Hans Christoph Steinhausen

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, 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 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 Bøcker Pedersen, Marianne Giørtz 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, Søren Dalsgaard, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Hans Christoph Steinhausen (Member of author group)

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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
Journal	Nature Genetics
Volume	51
Issue number	1
Pages (from-to)	63-75
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-018-0269-7
Publication status	Published - Jan 2019
Externally published	Yes

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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10.1038/s41588-018-0269-7

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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., Bækvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., Goldstein, J. I., Grasby, K. L., Grove, J., ... Steinhausen, H. C. (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{58447e166e8d4e489844fcfa2f1bcade,

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 = "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 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 S{\o}ren Dalsgaard and {ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and Steinhausen, {Hans Christoph}",

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 Research",

number = "1",

}

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, Stefansson, H, Stevens, C, Turley, P, Walters, GB, Won, H, Wright, MJ, Andreassen, OA, Asherson, P, Burton, CL, Boomsma, DI, Cormand, B, Dalsgaard, S, ADHD Working Group of the Psychiatric Genomics Consortium (PGC) & Steinhausen, HC 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, 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

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 Bøcker

AU - Pedersen, Marianne Giørtz

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, Søren

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

A2 - Steinhausen, Hans Christoph

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 - Adolescent

KW - Attention Deficit Disorder with Hyperactivity/genetics

KW - Brain/physiology

KW - Child

KW - Child, Preschool

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

U2 - 10.1038/s41588-018-0269-7

DO - 10.1038/s41588-018-0269-7

M3 - Journal article

C2 - 30478444

SN - 1061-4036

VL - 51

SP - 63

EP - 75

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

Abstract

Keywords

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