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

763 Citations (Web of Science)

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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Cite this

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

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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 = "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.}",

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",

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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.

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

VL - 51

SP - 63

EP - 75

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -