Cited by 2,203Attention Deficit Hyperactivity DisorderGenetic Associations and EpidemiologyAutism Spectrum Disorder Research

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

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ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Demontis, Ditte, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Walters, Raymond K., Martin, Joanna, Mattheisen, Manuel, Als, Thomas D. +76 more·2019·Nature Genetics

Published version of a preprint

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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Crossref · 10.1038/s41588-018-0269-7

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  • Variants within the dopamine transporter gene (DAT1/SLC6A3) and the dopamine D4 receptor gene (DRD4, especially the 7-repeat allele) are repeatedly associated with increased ADHD risk.

    “Variants within the dopamine transporter gene (DAT1/SLC6A3) and the dopamine D4 receptor gene (DRD4, especially the 7-repeat allele) were repeatedly associated with increased ADHD risk”

    From ADHD in Adulthood: Clinical Presentation, Comorbidities, and Treatment Perspectives (2025) · cites this paper as [59]

    The Results (Analysis of gene sets; page unavailable) report little evidence for effects in previously proposed ADHD candidate genes, with only SLC9A9 showing a weak association among the nine genes examined. The Discussion likewise says substantial effects were not observed in most previously reported candidate genes. The copy does not name DAT1/SLC6A3, DRD4, or the 7-repeat allele in these findings, so the contradiction is to the claim's broad assertion of repeated risk associations rather than a gene-specific result. (LLM, conf=0.73)

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  • Most ADHD cases are polygenic: numerous variants of very small effect together raise risk.

    “This study confirmed a polygenic cause for most cases of ADHD, meaning that many genetic variants, each having a very small effect, combine to increase risk for the disorder.”

    From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Demontis et al., 2019

    The Discussion reports modest effects for individual risk variants (odds ratios 1.077–1.198) and describes an important role for common variants in ADHD’s polygenic architecture. The Results section “Polygenic Architecture of ADHD” estimates SNP heritability, but neither passage establishes that polygenic risk causes most individual ADHD cases. The claim’s “most cases” qualifier therefore goes beyond the paper’s findings. (LLM, conf=0.87)

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  • ADHD shares some genetic and environmental influences with many psychiatric and somatic disorders.

    “Family, twin, and DNA studies show that genetic and environmental influences are partially shared between ADHD and many other psychiatric disorders (e.g. schizophrenia, depression, bipolar disorder, autism spectrum disorder, conduct disorder, eating disorders, and substance use disorders) and with somatic disorders (e.g. migraine and obesity)”

    From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Demontis et al., 2019

    The Introduction reports genetic overlap between ADHD and several psychiatric conditions, and the Results (Genetic correlation with other traits) report significant genetic overlap with depression, anorexia nervosa, and obesity-related phenotypes. The paper says environmental risks contribute to ADHD, but the cited passages do not establish that environmental influences are shared with those other disorders. They also do not substantiate every example in the citing sentence, including migraine. (LLM, conf=0.88)

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  • Cross-disorder genetic correlation estimates clearly show that there are substantial shared common genetic risks (e.g., across ADHD and ASD) and therefore future studies of specific SNPs that are implicated in multiple disorders will need to be identified through multi-disorder analyses.

    “Indeed, cross-disorder genetic correlation estimates clearly show that there are substantial shared common genetic risks (e.g., across ADHD and ASD) and therefore future studies of specific SNPs that are implicated in multiple disorders will need to be identified through multi-disorder analyses 52 .”

    From Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review (2023) · cites this paper as [52]

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  • Identified ADHD risk loci are enriched in genes expressed in the developing brain and involved in neurodevelopmental processes.

    “Identified loci are enriched in genes expressed in the developing brain and involved in neurodevelopmental processes”

    From ADHD in Adulthood: Clinical Presentation, Comorbidities, and Treatment Perspectives (2025) · cites this paper as [59]

    The Discussion says several ADHD loci lie in or near genes implicated in neurodevelopmental processes, including FOXP2, SORCS3 and DUSP6. But the Results (Polygenic Architecture of ADHD; Analysis of gene sets) report enrichment in central-nervous-system regulatory elements, not in genes expressed in the developing brain, and no Gene Ontology gene set remained significant after correction for multiple testing. The claimed enrichment in developing-brain-expressed genes is therefore not established by this copy. (LLM, conf=0.86)

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Research works printed but not linked: 1

  1. [128]Roadmap Epigenomics C Integrative analysis of 111 reference human epigenomes. Nature 518, 317– 330, doi: 10.1038/nature14248 (2015). 25693563 PMC4530010 · DOI · Paper page

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Authors
ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Demontis, D., Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, 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., Gudmundsson, O. O., Hansen, C. S., Hauberg, M. E., Hollegaard, M. V., Howrigan, D. P., Huang, H., Maller, J. B., Martin, A. R., Martin, N. G., Moran, J., Pallesen, J., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Poterba, T., Poulsen, J. B., Ripke, S., Robinson, E. B., Satterstrom, F. K., Stefansson, H., Stevens, C., Turley, P., Walters, G. B., Won, H., Wright, M. J., Andreassen, O. A., Asherson, P., Burton, C. L., Boomsma, D. I., Cormand, B., Dalsgaard, S., Franke, B., Gelernter, J., Geschwind, D., Hakonarson, H., Haavik, J., Kranzler, H. R., Kuntsi, J., Langley, K., Lesch, K.-P., Middeldorp, C., Reif, A., Rohde, L. A., Roussos, P., Schachar, R., Sklar, P., Sonuga-Barke, E. J. S., Sullivan, P. F., Thapar, A., Tung, J. Y., Waldman, I. D., Medland, S. E., Stefansson, K., Nordentoft, M., Hougaard, D. M., Werge, T., Mors, O., Mortensen, P. B., Daly, M. J., Faraone, S. V., Børglum, A. D., & Neale, B. M.
Affiliations
  • Aarhus University (DK)
  • Broad Institute (US)
  • National University Hospital of Iceland (IS)
  • 23andMe (United States) (US)
  • University of California, Los Angeles (US)
  • QIMR Berghofer Medical Research Institute (AU)
  • Statens Serum Institut (DK)
  • Harvard University (US)
  • deCODE Genetics (Iceland) (IS)
  • The University of Queensland (AU)
  • Oslo University Hospital (NO)
  • King's College London (GB)
  • University of Toronto (CA)
  • Amsterdam Neuroscience (NL)
  • Instituto de Salud Carlos III (ES)
  • Radboud University Medical Center (NL)
  • Veterans Health Administration (US)
  • Children's Hospital of Philadelphia (US)
  • Haukeland University Hospital (NO)
  • Mental Illness Research, Education and Clinical Centers (US)
  • Cardiff University (GB)
  • Sechenov University (RU)
  • University Hospital Frankfurt (DE)
  • James J. Peters VA Medical Center (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of North Carolina at Chapel Hill (US)
  • Emory University (US)
  • University of Copenhagen (DK)
  • Aarhus University Hospital (DK)
  • SUNY Upstate Medical University (US)
Corresponding author
  • Faraone, Stephen V.
  • Børglum, Anders D.
  • Neale, Benjamin M.
Venue
Nature Genetics
Published
2018-11-26
Volume
51
Issue
1
Pages
63-75
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2802815532
Cited by
2,203
References
148
Citations by year
2026: 121 · 2025: 209 · 2024: 275 · 2023: 307 · 2022: 347 · 2021: 315 · 2020: 290 · 2019: 230 · 2018: 91 · 2017: 15 · 2013: 1
FWCI
35.73
Type
journal article
Language
en
Open access
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  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
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Funders
  • U.S. Department of Veterans Affairs (BX002395)
  • Alzheimer's Association (NIRG-340998)
  • Amgen
  • Eli Lilly and Company
  • Pfizer (15/878)
  • Massachusetts General Hospital
  • Aarhus Universitet
  • Universität Basel
  • Philipps-Universität Marburg
  • University of Bern
  • Sunovion
  • Wellcome Trust (602450, 68341, 213694, 016-130-669, 106047/Z/14/Z, 106047, 223273)
  • Indivior
  • QIMR Berghofer Medical Research Institute
  • Broad Institute
  • American Society of Clinical Psychopharmacology
  • Action Medical Research
  • National Institute for Health and Care Research (NF-SI-0616-10040)
  • University of Southampton
  • King's College London (278948)
  • University of Oxford
  • European Commission
  • Cardiff University
  • University College Dublin
  • Deutsche Forschungsgemeinschaft (DFG CRC 1193, subproject Z03, 602805, CRC--1193, 667302, DFG CRC 1193)
  • Universität Heidelberg (602805)
  • Aalborg Universitet
  • Generalitat de Catalunya (2017-SGR, 2017/SGR738)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (602805, 602450, 016‐130‐669, 278948, 667302)
  • Ministerio de Economía y Competitividad (SAF2015-68341-R)
  • Lundbeckfonden (R208-2015-3951, R155-2014-1724, R102‐A9118, R248‐2017‐2003)
  • KU Leuven
  • Novo Nordisk
  • Universiteit Gent
  • Universitetet i Bergen (223273)
  • Háskóli Íslands
  • Norges Forskningsråd (223273, #249711, #213694, 248778)
  • Radboud Universitair Medisch Centrum
  • Universität Zürich
  • Universitätsklinikum Jena
  • European College of Neuropsychopharmacology
  • Peking University
  • Universität Duisburg-Essen
  • Novo Nordisk Fonden (NNF 16OC0022018)
  • Universitat Autònoma de Barcelona
  • Servier
  • Fundació Institut de Recerca Hospital Universitari Vall d’Hebron
  • H. Lundbeck A/S (R102-A9118, R155-2014-1724)
  • National Institutes of Health (389875, 1s10od018522-01, 223273, 5u01mh094432-04, H2020)
  • University of California, Los Angeles
  • Horizon 2020 Framework Programme (643051, 667302, R155-2014-1724)
  • Universitätsklinikum Tübingen
  • Canadian Institutes of Health Research (106573_1)
  • Medical Research Council (1R01MH107649-01, MR/L010305/1, MC_UU_00011/1)
  • Australian Research Council (DP0212016, DP0343921)
  • National Health and Medical Research Council (496739, 1103623, 443036, 389927, 389891, 552485, 552498, 442981, 389938, 1049894, 241944, 339462, 442915, 389875, 389892)
  • Agència de Gestió d'Ajuts Universitaris i de Recerca (2017-SGR-738)
  • Seventh Framework Programme (FP7/2007, 667302, FP7/2007‐2013, H2020, 278948, 643051, 602805, 602450)
  • Center for Sepsis Control and Care
  • National Institute on Aging (R01AG050986)
  • National Institute of Mental Health (U01MH109539, R01MH107649, U01 MH094432, R01MH109677, U01MH109536, R01MH094469, 016-130-669, R01MH101519, 5U01MH094432-04, R00MH113823)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K01DK114379)
  • David Geffen School of Medicine, University of California, Los Angeles
  • Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
  • FP7 Ideas: European Research Council (294838)
  • Cilag
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
attention deficit hyperactivity disorder, genetic susceptibility, genetic susceptibility loci, common genetic variants, educational attainment, heritability
MeSH terms
Adolescent, Attention Deficit Disorder with Hyperactivity, Brain, Child, Child, Preschool, Female, Gene Expression Regulation, Humans, Male, Risk, Cohort Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci

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