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; Jennifer Moran; Nicholas G Martin; 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; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Hans-Christoph E. Steinhausen; Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; 23andMe Research Team; Ole A Andreassen; Philip Asherson; Christie L Burton; Dorret I Boomsma; Bru Cormand; Søren Dalsgaard; Barbara Franke; Joel  Gelernter; Daniel  Geschwind; Hakon Hakonarson; Jan  Haavik; Henry R.  Kranzler; Jonna Kuntsi; Kate Langley; Klaus-Peter Lesch; Christel  Middeldorp; Andreas  Reif; Luis Augusto Rohde; Panos  Roussos; Russell Schachar; Pamela Sklar; Edmund J S Sonuga-Barke; Patrick F Sullivan; Anita Thapar; Joyce Y Tung; Irwin D.  Waldman; Sarah E Medland; Kari Stefansson; Merete Nordentoft; David M Hougaard; Thomas Werge; Ole Mors; Preben Bo Mortensen; Mark J Daly; Stephen V Faraone; Anders D Børglum; 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, 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, Jennifer Moran, Nicholas G Martin, 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, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Hans-Christoph E. Steinhausen (Medlem af forfattergruppering), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Ole A Andreassen, Philip Asherson, Christie L Burton, Dorret I Boomsma, Bru Cormand, Søren Dalsgaard, Barbara Franke, Joel Gelernter, Daniel Geschwind, Hakon Hakonarson, Jan Haavik, Henry R. Kranzler, Jonna Kuntsi, Kate Langley, Klaus-Peter Lesch, Christel Middeldorp, Andreas Reif, Luis Augusto Rohde, Panos Roussos, Russell Schachar, Pamela Sklar, Edmund J S Sonuga-Barke, Patrick F Sullivan, Anita Thapar, Joyce Y Tung, Irwin D. Waldman, Sarah E Medland, Kari Stefansson, Merete Nordentoft, David M Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Mark J Daly, Stephen V Faraone, Anders D Børglum, Benjamin M Neale

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

1166 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	51
Udgave nummer	1
Sider (fra-til)	63-75
Antal sider	13
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-018-0269-7
Status	Udgivet - jan. 2019

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10.1038/s41588-018-0269-7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481311/pdf/nihms-1002358.pdf

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Citationsformater

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., ... 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{2ea2ba33e51e4b07a628232327647cdd,

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 Jennifer Moran and Martin, {Nicholas G} 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 {ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and Steinhausen, {Hans-Christoph E.} and {Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium} and {23andMe Research Team} and Andreassen, {Ole A} and Philip Asherson and Burton, {Christie L} and Boomsma, {Dorret I} and Bru Cormand and S{\o}ren Dalsgaard and Barbara Franke and Joel Gelernter and Daniel Geschwind and Hakon Hakonarson and Jan Haavik and Kranzler, {Henry R.} and Jonna Kuntsi and Kate Langley and Klaus-Peter Lesch and Christel Middeldorp and Andreas Reif and Rohde, {Luis Augusto} and Panos Roussos and Russell Schachar and Pamela Sklar and Sonuga-Barke, {Edmund J S} and Sullivan, {Patrick F} and Anita Thapar and Tung, {Joyce Y} and Waldman, {Irwin D.} and Medland, {Sarah E} and Kari Stefansson and Merete Nordentoft and Hougaard, {David M} and Thomas Werge and Ole Mors and Mortensen, {Preben Bo} and Daly, {Mark J} and Faraone, {Stephen V} and B{\o}rglum, {Anders D} 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",

}

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, Moran, J, Martin, NG, 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, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Steinhausen, H-CE, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Andreassen, OA, Asherson, P, Burton, CL, Boomsma, DI, Cormand, B, Dalsgaard, S, Franke, B, Gelernter, J, Geschwind, D, Hakonarson, H, Haavik, J, Kranzler, HR, Kuntsi, J, Langley, K, Lesch, K-P, Middeldorp, C, Reif, A, Rohde, LA, Roussos, P, Schachar, R, Sklar, P, Sonuga-Barke, EJS, Sullivan, PF, Thapar, A, Tung, JY, Waldman, ID, Medland, SE, Stefansson, K, Nordentoft, M, Hougaard, DM, Werge, T, Mors, O, Mortensen, PB, Daly, MJ, Faraone, SV, Børglum, AD & Neale, BM 2019, 'Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder', Nature Genetics, bind 51, nr. 1, s. 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 - Moran, Jennifer

AU - Martin, Nicholas G

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

AU - Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

AU - 23andMe Research Team

AU - Andreassen, Ole A

AU - Asherson, Philip

AU - Burton, Christie L

AU - Boomsma, Dorret I

AU - Cormand, Bru

AU - Dalsgaard, Søren

AU - Franke, Barbara

AU - Gelernter, Joel

AU - Geschwind, Daniel

AU - Hakonarson, Hakon

AU - Haavik, Jan

AU - Kranzler, Henry R.

AU - Kuntsi, Jonna

AU - Langley, Kate

AU - Lesch, Klaus-Peter

AU - Middeldorp, Christel

AU - Reif, Andreas

AU - Rohde, Luis Augusto

AU - Roussos, Panos

AU - Schachar, Russell

AU - Sklar, Pamela

AU - Sonuga-Barke, Edmund J S

AU - Sullivan, Patrick F

AU - Thapar, Anita

AU - Tung, Joyce Y

AU - Waldman, Irwin D.

AU - Medland, Sarah E

AU - Stefansson, Kari

AU - Nordentoft, Merete

AU - Hougaard, David M

AU - Werge, Thomas

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Daly, Mark J

AU - Faraone, Stephen V

AU - Børglum, Anders D

AU - Neale, Benjamin M

A2 - Steinhausen, Hans-Christoph E.

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

UR - http://www.scopus.com/inward/record.url?scp=85057436335&partnerID=8YFLogxK

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

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