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

23andMe Research Team; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

doi:10.1038/s41588-018-0269-7

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

23andMe Research Team, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

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

1360 Citations (Scopus)

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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
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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@article{2c51033f21b94a76826920492f18bcba,

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 = "{23andMe Research Team} and {ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and {Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium} and 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 {\"O}zg{\"u}r Albayrak and Anney, {Richard J.L.} and Arranz, {Maria Jes{\'u}s} and Banaschewski, {Tobias J.} and Claiton Bau and Joseph Biederman and Buitelaar, {Jan K.} and Miguel Casas and Alice Charach and Jennifer Crosbie and Astrid Dempfle and Doyle, {Alysa E.} and Ebstein, {Richard P.} and Josephine Elia and Christine Freitag and Manuel F{\"o}cker and Michael Gill and Eugenio Grevet and Ziarih Hawi and Johannes Hebebrand and Beate Herpertz-Dahlmann and Amaia Hervas and Anke Hinney and Sarah Hohmann and Peter Holmans and Mara Hutz and Abel Ickowitz and Stefan Johansson and Lindsey Kent and Sarah Kittel-Schneider and Nanda Lambregts-Rommelse and Gerd Lehmkuhl and Loo, {Sandra K.} and McGough, {James J.} and Jobst Meyer and Eric Mick and Frank Middletion and Ana Miranda and Mota, {Nina Roth} and Fernando Mulas and Aisling Mulligan and Freimer Nelson and Nguyen, {T. Trang} and Oades, {Robert D.} and O{\textquoteright}Donovan, {Michael C.} and Owen, {Michael J.} and Haukur Palmason and Ramos-Quiroga, {Josep Antoni} and Renner, {Tobias J.} and Marta Ribas{\'e}s and Marcella Rietschel and Olga Rivero and Jasmin Romanos and Marcel Romanos and Aribert Rothenberger and Herbert Royers and Christina S{\'a}nchez-Mora and Andr{\'e} Scherag and Schimmelmann, {Benno G.} and Helmut Sch{\"a}fer and Joseph Sergeant and Judith Sinzig and Smalley, {Susan L.} and Steinhausen, {Hans Christoph} and Margaret Thompson and Alexandre Todorov and Vasquez, {Alejandro Arias} and Susanne Walitza and Yufeng Wang and Andreas Warnke and Nigel Williams and Witt, {Stephanie H.} and Li Yang and Tetyana Zayats and Yanli Zhang-James and Smith, {George Davey} and Davies, {Gareth E.} and Ehli, {Erik A.} and Evans, {David M.} and Fedko, {Iryna O.} and Greven, {Corina U.} and Groen-Blokhuis, {Maria M.} and Monica Guxens and Hammerschlag, {Anke R.} and Hartman, {Catharina A.} and Joachim Heinrich and {Jan Hottenga}, Jouke and James Hudziak and Astanand Jugessur and Kemp, {John P.} and Eva Krapohl and Mario Murcia and Ronny Myhre and Nolte, {Ilja M.} and Nyholt, {Dale R.} and Johan Ormel and Ouwens, {Klaasjan G.} and Irene Pappa and Pennell, {Craig E.} and Robert Plomin and Susan Ring and Marie Standl and Evie Stergiakouli and Pourcain, {Beate St} and Camilla Stoltenberg and Jordi Sunyer and Elisabeth Thiering and Henning Tiemeier and Tiesler, {Carla M.T.} and Timpson, {Nicholas J.} and Maciej Trzaskowski and {van der Most}, {Peter Johannes} and Natalia Vilor-Tejedor and Wang, {Carol A.} and Whitehouse, {Andrew J.O.} and Huiying Zhao and Michelle Agee and Babak Alipanahi and Adam Auton and Bell, {Robert K.} and Katarzyna Bryc and Elson, {Sarah L.} and Pierre Fontanillas and Furlotte, {Nicholas A.} and Hinds, {David A.} and Hromatka, {Bethann S.} and Huber, {Karen E.} and Aaron Kleinman and Litterman, {Nadia K.} and McIntyre, {Matthew H.} and Mountain, {Joanna L.} and Northover, {Carrie A.M.} and Pitts, {Steven J.} and Sathirapongsasuti, {J. Fah} and Sazonova, {Olga V.} and Shelton, {Janie F.} and Suyash Shringarpure and Chao Tian and Vladimir Vacic and Wilson, {Catherine H.} 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 Lesch, {Klaus Peter} 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,

day = "1",

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

language = "English",

volume = "51",

pages = "63--75",

journal = "Nature Genetics",

issn = "1546-1718",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "1",

}

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. / 23andMe Research Team; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium.
In: Nature Genetics, Vol. 51, No. 1, 01.01.2019, p. 63-75.

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

TY - JOUR

T1 - Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

AU - 23andMe Research Team

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

AU - Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

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 - Albayrak, Özgür

AU - Anney, Richard J.L.

AU - Arranz, Maria Jesús

AU - Banaschewski, Tobias J.

AU - Bau, Claiton

AU - Biederman, Joseph

AU - Buitelaar, Jan K.

AU - Casas, Miguel

AU - Charach, Alice

AU - Crosbie, Jennifer

AU - Dempfle, Astrid

AU - Doyle, Alysa E.

AU - Ebstein, Richard P.

AU - Elia, Josephine

AU - Freitag, Christine

AU - Föcker, Manuel

AU - Gill, Michael

AU - Grevet, Eugenio

AU - Hawi, Ziarih

AU - Hebebrand, Johannes

AU - Herpertz-Dahlmann, Beate

AU - Hervas, Amaia

AU - Hinney, Anke

AU - Hohmann, Sarah

AU - Holmans, Peter

AU - Hutz, Mara

AU - Ickowitz, Abel

AU - Johansson, Stefan

AU - Kent, Lindsey

AU - Kittel-Schneider, Sarah

AU - Lambregts-Rommelse, Nanda

AU - Lehmkuhl, Gerd

AU - Loo, Sandra K.

AU - McGough, James J.

AU - Meyer, Jobst

AU - Mick, Eric

AU - Middletion, Frank

AU - Miranda, Ana

AU - Mota, Nina Roth

AU - Mulas, Fernando

AU - Mulligan, Aisling

AU - Nelson, Freimer

AU - Nguyen, T. Trang

AU - Oades, Robert D.

AU - O’Donovan, Michael C.

AU - Owen, Michael J.

AU - Palmason, Haukur

AU - Ramos-Quiroga, Josep Antoni

AU - Renner, Tobias J.

AU - Ribasés, Marta

AU - Rietschel, Marcella

AU - Rivero, Olga

AU - Romanos, Jasmin

AU - Romanos, Marcel

AU - Rothenberger, Aribert

AU - Royers, Herbert

AU - Sánchez-Mora, Christina

AU - Scherag, André

AU - Schimmelmann, Benno G.

AU - Schäfer, Helmut

AU - Sergeant, Joseph

AU - Sinzig, Judith

AU - Smalley, Susan L.

AU - Steinhausen, Hans Christoph

AU - Thompson, Margaret

AU - Todorov, Alexandre

AU - Vasquez, Alejandro Arias

AU - Walitza, Susanne

AU - Wang, Yufeng

AU - Warnke, Andreas

AU - Williams, Nigel

AU - Witt, Stephanie H.

AU - Yang, Li

AU - Zayats, Tetyana

AU - Zhang-James, Yanli

AU - Smith, George Davey

AU - Davies, Gareth E.

AU - Ehli, Erik A.

AU - Evans, David M.

AU - Fedko, Iryna O.

AU - Greven, Corina U.

AU - Groen-Blokhuis, Maria M.

AU - Guxens, Monica

AU - Hammerschlag, Anke R.

AU - Hartman, Catharina A.

AU - Heinrich, Joachim

AU - Jan Hottenga, Jouke

AU - Hudziak, James

AU - Jugessur, Astanand

AU - Kemp, John P.

AU - Krapohl, Eva

AU - Murcia, Mario

AU - Myhre, Ronny

AU - Nolte, Ilja M.

AU - Nyholt, Dale R.

AU - Ormel, Johan

AU - Ouwens, Klaasjan G.

AU - Pappa, Irene

AU - Pennell, Craig E.

AU - Plomin, Robert

AU - Ring, Susan

AU - Standl, Marie

AU - Stergiakouli, Evie

AU - Pourcain, Beate St

AU - Stoltenberg, Camilla

AU - Sunyer, Jordi

AU - Thiering, Elisabeth

AU - Tiemeier, Henning

AU - Tiesler, Carla M.T.

AU - Timpson, Nicholas J.

AU - Trzaskowski, Maciej

AU - van der Most, Peter Johannes

AU - Vilor-Tejedor, Natalia

AU - Wang, Carol A.

AU - Whitehouse, Andrew J.O.

AU - Zhao, Huiying

AU - Agee, Michelle

AU - Alipanahi, Babak

AU - Auton, Adam

AU - Bell, Robert K.

AU - Bryc, Katarzyna

AU - Elson, Sarah L.

AU - Fontanillas, Pierre

AU - Furlotte, Nicholas A.

AU - Hinds, David A.

AU - Hromatka, Bethann S.

AU - Huber, Karen E.

AU - Kleinman, Aaron

AU - Litterman, Nadia K.

AU - McIntyre, Matthew H.

AU - Mountain, Joanna L.

AU - Northover, Carrie A.M.

AU - Pitts, Steven J.

AU - Sathirapongsasuti, J. Fah

AU - Sazonova, Olga V.

AU - Shelton, Janie F.

AU - Shringarpure, Suyash

AU - Tian, Chao

AU - Vacic, Vladimir

AU - Wilson, Catherine H.

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.

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 - Article

C2 - 30478444

AN - SCOPUS:85057436335

SN - 1546-1718

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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