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

Ditte Demontis, Raymond K. Walters, Joanna Martin, Mattheisen Manuel, Thomas Als, Esben Agerbo, Gisli 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 & 3 others ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team

Research output: Contribution to journalArticleResearchpeer-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 languageEnglish
Number of pages16
JournalNature Genetics
Volume51
Issue number1
DOIs
Publication statusPublished - Jan 2019

Keywords

  • ADHD
  • genome-wide association studies

Cite this

Demontis, D., Walters, R. K., Martin, J., Manuel, M., Als, T., Agerbo, E., ... 23andMe Research Team (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics, 51(1). https://doi.org/10.1038/s41588-018-0269-7
Demontis, Ditte ; Walters, Raymond K. ; Martin, Joanna ; Manuel, Mattheisen ; Als, Thomas ; Agerbo, Esben ; Baldursson, Gisli ; 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. ; ADHD Working Group of the Psychiatric Genomics Consortium (PGC) ; Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium ; 23andMe Research Team. / Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. In: Nature Genetics. 2019 ; Vol. 51, No. 1.
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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.",
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Demontis, D, Walters, RK, Martin, J, Manuel, M, Als, T, 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, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium & 23andMe Research Team 2019, 'Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder' Nature Genetics, vol. 51, no. 1. 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; Manuel, Mattheisen; Als, Thomas ; Agerbo, Esben ; Baldursson, Gisli; 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.; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; 23andMe Research Team.

In: Nature Genetics, Vol. 51, No. 1, 01.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Agerbo, Esben

AU - Baldursson, Gisli

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

AU - Hawi, Ziarih

AU - Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

AU - 23andMe Research Team

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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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M3 - Article

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