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; G. sli 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 B. cker 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; Özgür Albayrak; T. Trang Nguyen; David M. Evans; Maria M. Groen-Blokhuis; Anke R. Hammerschlag; Christel Middeldorp; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Andreas Reif; Luis Augusto Rohde; Panos Roussos; Russell Schachar; Edmund J. S. Sonuga-Barke; Patrick Sullivan; Anita Thapar; Joyce Y. Tung; Irwin D. Waldman; Sarah E. Medland; 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, G. sli 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 B. cker 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, Özgür Albayrak, T. Trang Nguyen, David M. Evans, Maria M. Groen-Blokhuis, Anke R. Hammerschlag, Christel Middeldorp, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Andreas Reif, Luis Augusto Rohde, Panos Roussos, Russell Schachar, Edmund J. S. Sonuga-Barke, Patrick Sullivan, Anita Thapar, Joyce Y. Tung, Irwin D. Waldman, Sarah E. Medland, Ole Mors, Preben Bo Mortensen, Mark J. Daly, Stephen V. Faraone, Anders D. Børglum, Benjamin M. Neale

Psychiatry

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

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
DOIs	https://doi.org/10.1038/s41588-018-0269-7
Publication status	Published - 1 Jan 2019

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Demontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G. S., 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

Demontis, Ditte ; Walters, Raymond K. ; Martin, Joanna ; Mattheisen, Manuel ; Als, Thomas D. ; Agerbo, Esben ; Baldursson, G. sli ; Belliveau, Rich ; Bybjerg-Grauholm, Jonas ; Bækvad-Hansen, Marie ; Cerrato, Felecia ; Chambert, Kimberly ; Churchhouse, Claire ; Dumont, Ashley ; Eriksson, Nicholas ; Gandal, Michael ; Goldstein, Jacqueline I. ; Grasby, Katrina L. ; Grove, Jakob ; Gudmundsson, Olafur O. ; Hansen, Christine S. ; Hauberg, Mads Engel ; Hollegaard, Mads V. ; Howrigan, Daniel P. ; Huang, Hailiang ; Maller, Julian B. ; Martin, Alicia R. ; Martin, Nicholas G. ; Moran, Jennifer ; Pallesen, Jonatan ; Palmer, Duncan S. ; Pedersen, Carsten B. cker ; Pedersen, Marianne Giørtz ; Poterba, Timothy ; Poulsen, Jesper Buchhave ; Ripke, Stephan ; Robinson, Elise B. ; Satterstrom, F. Kyle ; Stefansson, Hreinn ; Stevens, Christine ; Turley, Patrick ; Walters, G. Bragi ; Won, Hyejung ; Wright, Margaret J. ; Albayrak, Özgür ; Nguyen, T. Trang ; Evans, David M. ; Groen-Blokhuis, Maria M. ; Hammerschlag, Anke R. ; Middeldorp, Christel ; ADHD Working Group of the Psychiatric Genomics Consortium (PGC) ; Reif, Andreas ; Rohde, Luis Augusto ; Roussos, Panos ; Schachar, Russell ; Sonuga-Barke, Edmund J. S. ; Sullivan, Patrick ; Thapar, Anita ; Tung, Joyce Y. ; Waldman, Irwin D. ; Medland, Sarah E. ; Mors, Ole ; Bo Mortensen, Preben ; Daly, Mark J. ; Faraone, Stephen V. ; Børglum, Anders D. ; Neale, Benjamin M. / Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. In: Nature Genetics. 2019 ; Vol. 51, No. 1. pp. 63-75.

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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.",

author = "Ditte Demontis and Walters, {Raymond K.} and Joanna Martin and Manuel Mattheisen and Als, {Thomas D.} and Esben Agerbo and Baldursson, {G. sli} 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. 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 {\"O}zg{\"u}r Albayrak and Nguyen, {T. Trang} and Evans, {David M.} and Groen-Blokhuis, {Maria M.} and Hammerschlag, {Anke R.} and Christel Middeldorp and {ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and Andreas Reif and Rohde, {Luis Augusto} and Panos Roussos and Russell Schachar and Sonuga-Barke, {Edmund J. S.} and Patrick Sullivan and Anita Thapar and Tung, {Joyce Y.} and Waldman, {Irwin D.} and Medland, {Sarah E.} and Ole Mors and {Bo Mortensen}, Preben and Daly, {Mark J.} and Faraone, {Stephen V.} and B{\o}rglum, {Anders D.} and Neale, {Benjamin M.}",

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doi = "10.1038/s41588-018-0269-7",

language = "English",

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Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, GS, 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, CBC, Pedersen, MG, Poterba, T, Poulsen, JB, Ripke, S, Robinson, EB, Satterstrom, FK, Stefansson, H, Stevens, C, Turley, P, Walters, GB, Won, H, Wright, MJ, Albayrak, Ö, Nguyen, TT, Evans, DM, Groen-Blokhuis, MM, Hammerschlag, AR, Middeldorp, C, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Reif, A, Rohde, LA, Roussos, P, Schachar, R, Sonuga-Barke, EJS, Sullivan, P, Thapar, A, Tung, JY, Waldman, ID, Medland, SE, Mors, O, Bo Mortensen, P, 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, 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. / Demontis, Ditte; Walters, Raymond K.; Martin, Joanna; Mattheisen, Manuel; Als, Thomas D.; Agerbo, Esben; Baldursson, G. sli; Belliveau, Rich; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Churchhouse, Claire; Dumont, Ashley; Eriksson, Nicholas; Gandal, Michael; Goldstein, Jacqueline I.; Grasby, Katrina L.; Grove, Jakob; Gudmundsson, Olafur O.; Hansen, Christine S.; Hauberg, Mads Engel; Hollegaard, Mads V.; Howrigan, Daniel P.; Huang, Hailiang; Maller, Julian B.; Martin, Alicia R.; Martin, Nicholas G.; Moran, Jennifer; Pallesen, Jonatan; Palmer, Duncan S.; Pedersen, Carsten B. cker; Pedersen, Marianne Giørtz; Poterba, Timothy; Poulsen, Jesper Buchhave; Ripke, Stephan; Robinson, Elise B.; Satterstrom, F. Kyle; Stefansson, Hreinn; Stevens, Christine; Turley, Patrick; Walters, G. Bragi; Won, Hyejung; Wright, Margaret J.; Albayrak, Özgür; Nguyen, T. Trang; Evans, David M.; Groen-Blokhuis, Maria M.; Hammerschlag, Anke R.; Middeldorp, Christel; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Reif, Andreas; Rohde, Luis Augusto; Roussos, Panos; Schachar, Russell; Sonuga-Barke, Edmund J. S.; Sullivan, Patrick; Thapar, Anita; Tung, Joyce Y.; Waldman, Irwin D.; Medland, Sarah E.; Mors, Ole; Bo Mortensen, Preben; Daly, Mark J.; Faraone, Stephen V.; Børglum, Anders D.; Neale, Benjamin M.

In: Nature Genetics, Vol. 51, No. 1, 01.01.2019, p. 63-75.

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

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, G. sli

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 B. cker

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 - Albayrak, Özgür

AU - Nguyen, T. Trang

AU - Evans, David M.

AU - Groen-Blokhuis, Maria M.

AU - Hammerschlag, Anke R.

AU - Middeldorp, Christel

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

AU - Reif, Andreas

AU - Rohde, Luis Augusto

AU - Roussos, Panos

AU - Schachar, Russell

AU - Sonuga-Barke, Edmund J. S.

AU - Sullivan, Patrick

AU - Thapar, Anita

AU - Tung, Joyce Y.

AU - Waldman, Irwin D.

AU - Medland, Sarah E.

AU - Mors, Ole

AU - Bo Mortensen, Preben

AU - Daly, Mark J.

AU - Faraone, Stephen V.

AU - Børglum, Anders D.

AU - Neale, Benjamin M.

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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.

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DO - 10.1038/s41588-018-0269-7

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VL - 51

SP - 63

EP - 75

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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

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