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Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes

  • Camiel M. van der Laan*
  • , Hill F. Ip
  • , Marijn Schipper
  • , Jouke Jan Hottenga
  • , Beate St Pourcain
  • , Tetyana Zayats
  • , René Pool
  • , Eva M.L. Krapohl
  • , Isabell Brikell
  • , María Soler Artigas
  • , Judit Cabana-Domínguez
  • , Ilja M. Nolte
  • , Koen Bolhuis
  • , Teemu Palviainen
  • , Hadi Zafarmand
  • , Scott Gordon
  • , Fazil Aliev
  • , S. Alexandra Burt
  • , Carol A. Wang
  • , Gretchen Saunders
    • Ville Karhunen, Daniel E. Adkins, Richard Border, Roseann E. Peterson, Joseph A. Prinz, Elisabeth Thiering, Natàlia Vilor-Tejedor, Tarunveer S. Ahluwalia, Andrea Allegrini, Kaili Rimfeld, Qi Chen, Yi Lu, Joanna Martin, Rosa Bosch, Josep Antoni Ramos-Quiroga, Alexander Neumann, Judith Ensink, Katrina L. Grasby, José J. Morosoli, Xiaoran Tong, Shelby Marrington, James G. Scott, Andrey A. Shabalin, Robin Corley, Luke M. Evans, Karen Sugden, Silvia Alemany, Lærke Sass, Rebecca Vinding, Erik A. Ehli, Fiona A. Hagenbeek, Eske M. Derks, Henrik Larsson, Harold Snieder, Charlotte Cecil, Alyce M. Whipp, Tellervo Korhonen, Eero Vuoksimaa, Richard J. Rose, André G. Uitterlinden, Jan Haavik, Jennifer R. Harris, Øyvind Helgeland, Stefan Johansson, Gun Peggy S. Knudsen, Pal Rasmus Njolstad, Qing Lu, Alina Rodriguez, Anjali K. Henders, Abdullah Mamun, Jackob M. Najman, Sandy Brown, Christian Hopfer, Kenneth Krauter, Chandra A. Reynolds, Andrew Smolen, Michael Stallings, Sally Wadsworth, Tamara L. Wall, Lindon Eaves, Judy L. Silberg, Allison Miller, Alexandra Havdahl, Sabrina Llop, Maria Jose Lopez-Espinosa, Klaus Bønnelykke, Jordi Sunyer, Louise Arseneault, Marie Standl, Joachim Heinrich, Joseph Boden, John Pearson, John Horwood, Martin Kennedy, Richie Poulton, Hermine H. Maes, John Hewitt, William E. Copeland, Christel M. Middeldorp, Gail M. Williams, Naomi Wray, Marjo Riitta Järvelin, Matt McGue, William Iacono, Avshalom Caspi, Terrie E. Moffitt, Andrew J.O. Whitehouse, Craig E. Pennell, Kelly L. Klump, Chang Jiang, Danielle M. Dick, Ted Reichborn-Kjennerud, Nicholas G. Martin, Sarah E. Medland, Tanja Vrijkotte, Jaakko Kaprio, Henning Tiemeier, George Davey Smith, Catharina A. Hartman, Albertine J. Oldehinkel, Miquel Casas, Marta Ribasés, Paul Lichtenstein, Sebastian Lundström, Robert Plomin, Meike Bartels, Michel G. Nivard, Dorret I. Boomsma, Natalia Llonga
*Corresponding author for this work
  • Vrije Universiteit Amsterdam
  • MRC Integrative Epidemiology Unit
  • Max Planck Institute for Psycholinguistics
  • Radboud University Nijmegen
  • University of Bergen
  • Harvard University
  • Broad Institute
  • King's College London
  • Karolinska Institutet
  • CIBER - Center for Biomedical Research Network
  • Autonomous University of Barcelona
  • University of Barcelona
  • University of Groningen
  • Erasmus University Rotterdam
  • University of Helsinki
  • University of Amsterdam
  • Queensland Institute of Medical Research
  • Rutgers - The State University of New Jersey, New Brunswick
  • Michigan State University
  • School of Medicine and Public Health
  • Hunter Medical Research Institute
  • University of Minnesota Twin Cities
  • MRC Centre for Environment and Health
  • University of Oulu
  • University of Utah
  • University of California at Los Angeles
  • SUNY Downstate Health Sciences University
  • Virginia Commonwealth University
  • Duke University
  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • Ludwig Maximilian University of Munich
  • Pasqual Maragall Foundation
  • Centre for Genomic Regulation
  • Pompeu Fabra University
  • University of Copenhagen
  • Novo Nordisk A/S
  • Royal Holloway University of London
  • SJD Barcelona Children's Hospital
  • Amsterdam UMC
  • Levvel
  • University College London
  • University of Queensland
  • University of Kentucky
  • Queensland Health
  • Queensland Centre for Mental Health Research
  • University of Colorado Boulder
  • Avera Health
  • Örebro University
  • Leiden University
  • Centre for Biosystems Genomics Centre of Excellence
  • Norwegian Institute of Public Health
  • University of Florida
  • Anglia Ruskin University
  • Agency for Science, Technology and Research
  • National University of Singapore
  • University of California at San Diego
  • University of Colorado Denver
  • University of California at Riverside
  • University of Otago
  • Lovisenberg Diaconal Hospital
  • Jaume I University
  • University of Valencia
  • Barcelona Institute for Global Health
  • University of Melbourne
  • University of Vermont
  • Amsterdam Reproduction & Development Research Institute
  • Arkin Mental Health Care
  • Brunel University London
  • Telethon Kids Institute
  • University of Oslo
  • Queensland University of Technology
  • Bristol Medical School
  • Fundació d’Investigació Sant Pau
  • Instituto para el Desarrollo de Terapias Avanzadas en Neurociencias (IDETAN)
  • Region Skåne
  • University of Gothenburg

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

Abstract

We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHDSYMP). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHDOVERALL). ADHDSYMP returned no genome-wide significant variants. We show that the combined ADHDOVERALL GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (rg < −0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHDOVERALL outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

Original languageEnglish
Pages (from-to)2427-2435
Number of pages9
JournalNature Genetics
Volume57
Issue number10
Early online date17 Sept 2025
DOIs
Publication statusPublished - Oct 2025

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

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    • 6 Citations
    • 1 Comment/Letter to the editor

    • Publisher Correction: Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes

      van der Laan, C. M., Ip, H. F., Schipper, M., Hottenga, J.-J., St Pourcain, B., Zayats, T., Pool, R., Krapohl, E. M. L., Brikell, I., Soler Artigas, M., Cabana-Dominguez, J., Llonga, N., Nolte, I. M., Bolhuis, K., Palviainen, T., Zafarmand, H., Gordon, S., Aliev, F., Burt, S. A. & Wang, C. A. & 109 others, Saunders, G., Karhunen, V., Adkins, D. E., Border, R., Peterson, R. E., Prinz, J. A., Thiering, E., Vilor-Tejedor, N., Ahluwalia, T. S., Allegrini, A., Rimfeld, K., Chen, Q., Lu, Y., Martin, J., Bosch, R., Ramos-Quiroga, J. A., Neumann, A., Ensink, J., Grasby, K. L., Morosoli, J. J., Tong, X., Marrington, S., Scott, J. G., Shabalin, A. A., Corley, R., Evans, L. M., Sugden, K., Alemany, S., Sass, L., Vinding, R., Ehli, E. A., Hagenbeek, F. A., Derks, E. M., Larsson, H., Snieder, H., Cecil, C., Whipp, A. M., Korhonen, T., Vuoksimaa, E., Rose, R. J., Uitterlinden, A. G., Haavik, J., Harris, J. R., Helgeland, O., Johansson, S., Knudsen, G. P. S., Njolstad, P. R., Lu, Q., Rodriguez, A., Henders, A. K., Mamun, A., Najman, J. M., Brown, S., Hopfer, C., Krauter, K., Reynolds, C. A., Smolen, A., Stallings, M., Wadsworth, S., Wall, T. L., Eaves, L., Silberg, J. L., Miller, A., Havdahl, A., Llop, S., Lopez-Espinosa, M.-J., Bonnelykke, K., Sunyer, J., Arseneault, L., Standl, M., Heinrich, J., Boden, J., Pearson, J., Horwood, J., Kennedy, M., Poulton, R., Maes, H. H., Hewitt, J., Copeland, W. E., Middeldorp, C. M., Williams, G. M., Wray, N., Jarvelin, M.-R., Mcgue, M., Iacono, W., Caspi, A., Moffitt, T. E., Whitehouse, A. J. O., Pennell, C. E., Klump, K. L., Jiang, C., Dick, D. M., Reichborn-Kjennerud, T., Martin, N. G., Medland, S. E., Vrijkotte, T., Kaprio, J., Tiemeier, H., Davey Smith, G., Hartman, C. A., Oldehinkel, A. J., Casas, M., Ribases, M., Lichtenstein, P., Lundstrom, S., Plomin, R., Bartels, M., Nivard, M. G. & Boomsma, D. I., 29 Sept 2025, In: Nature Genetics. 57, p. 2604 1 p.

      Research output: Contribution to journal › Comment/Letter to the editor › Academic › peer-review

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