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; 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, 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, 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

Landspitali - The National University Hospital of Iceland

Research output: Contribution to journal › Article › 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
Journal	Nature Genetics
DOIs	https://doi.org/10.1038/s41588-018-0269-7
Publication status	Published - 1 Jan 2019

Other keywords

ADHD
Gen
Attention Deficit Disorder with Hyperactivity
Genome-Wide Association Study

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10.1038/s41588-018-0269-7

https://www.nature.com/articles/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., ... Neale, B. M. (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics. 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.",

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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, 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. 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 - 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

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.

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 - ADHD

KW - Gen

KW - Attention Deficit Disorder with Hyperactivity

KW - Genome-Wide Association Study

KW - ADHD

KW - Gen

KW - Attention Deficit Disorder with Hyperactivity

KW - Genome-Wide Association Study

U2 - 10.1038/s41588-018-0269-7

DO - 10.1038/s41588-018-0269-7

M3 - Article

C2 - 30478444

SN - 1546-1718

JO - Nature Genetics

JF - Nature Genetics

ER -

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

Abstract

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