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.
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Data availability
Summary statistics for ADHDSYMP and ADHDOVERALL are available for download through GWAS Catalog (ebi.ac.uk/gwas/studies/GCST90568440 and ebi.ac.uk/gwas/studies/GCST90568441). ADHDDIAG summary statistics are available for download at the Psychiatric Genomics Consortium (PGC) website (https://www.med.unc.edu/pgc/download-results/). Raw data are available upon request through the individual participating cohorts. Individual cohort GWAS summary statistics are available upon request through the corresponding author. Datasets used for gene mapping and hypergeometric gene-set tests in FUMA are listed in Supplementary Methods.
Code availability
The complete analysis plan is available for download at https://www.action-euproject.eu/sites/default/files/Action%20AGG%20AP%20SOP.pdf. The N-weighted GWAMA code is available via GitHub at https://github.com/baselmans/multivariate_GWAMA and via Zenodo at https://doi.org/10.5281/zenodo.15862079 (ref. 44. For a list of software and versions used, see Supplementary Methods.
Change history
29 September 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41588-025-02383-z
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Acknowledgements
We would like to thank all participants, their parents and teachers for making this study possible. This project was supported by the ACTION project. ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement 602768. Cohort-specific acknowledgments and funding information are included in the Supplementary Note.
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C.M.v.d.L. conducted the central analyses and wrote the manuscript. M. Schipper performed the FLAMES analyses. H.F.I., B.St.P., T.Z., R. Pool, E.M.L.K., I.B., M.S.A., J.C.-D., S.A., I.M.N., K.B., T.P., H.Z., S.G., F.A., C.A.W., G.S., V.K., D.E.A., R. Border, R.E.P., J.A.P., E.T., N.V.-T., T.K., E.V., A.K.H., S. Llop, M.-J.L.-E., C.J., D.M.D., T.S.A., A.A., K.R., Q.C., Y.L., J.M., R. Bosch, N.L., A.N., J.E., K.L.G., J.J.M., X.T., S.M., J.G.S., A.A.S., L.M.E., K.S., L.S., R.V., C.J., Q.L., J.P., J. Horwood and W.E.C. performed cohort-specific analyses. J.-J.H., R.C., S.J., M.S.A., J.C.-D., S.A., R. Bosch, N.L., S.A.B., C.C., J. Haavik, A.K.H., A.S., S. Llop, M.-J.L.-E., L.A., M.M., N.V.-T., E.A.E., K.K., M. Stallings and M.R. coordinated genotyping. B.St.P., S.A., J.S., H.L., S. Lundström, R.J.R., A.G.U., F.A.H., H.S., Ø.H., A.R., A.K.H., S. Llop, M.-J.L.-E., L.A., M.K., M.M., J.R.H., G.P.S.K., P.R.N., A. Mamun, J.M.N., S.B., C.H., C.A.R., M. Stallings, S.W., T.L.W., L.E., J.L.S., A. Miller, A.H., K.B., J.S., M. Standl, J. Heinrich, J.B., J. Horwood, R. Pool, H.H.M., W.E.C., C.M.M, N.W., M.-R.J., W.I., A.C., T.E.M., A.J.O.W., C.E.P., K.L.K., D.M.D., M.S.A., J.C.-D., S.A., R. Bosch, N.L., S.A.B., J.A.R.-Q., R.C., A.M.W., T.K., E.V., T.R.-K., N.G.M., S.E.M., T.V., J.K., H.T., C.A.H., A.J.O., M.C., P.L., R. Pool, M.B., M.G.N. and D.I.B. collected samples and conducted phenotyping. B.St.P., J.S., H.L., S. Lundström, S.A.B., R.J.R., A.G.U., J.R.H., G.P.S.K., P.R.N., J.M.N., S.B., C.H., J. Hewitt, M. Stallings, S.W., L.E., J.L.S., H.H.M., W.E.C., C.M.M., N.W., M.-R.J., W.I., A.C., T.E.M., A.J.O.W., C.E.P., KL.K., D.M.D., J.A.R.-Q., H.S., A.S., S. Llop, M.-J.L.-E., L.A., M.K., G.M.W., M.M., G.M.W., T.R.-K., N.G.M., S.E.M., T.V., J.K., H.T., G.D.S., C.A.T., A.J.O., M.C., M.R., P.L., R. Plomin, M.B., M.G.N. and D.I.B. led the study design and principal investigator oversight. All above mentioned authors and E.M.D. contributed to critical revisions of the manuscript and approved the final version for submission.
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J.A.R.-Q. was on the speakers’ bureau and/or acted as a consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, BMS, Medice, Rubió, Uriach, Technofarma and Raffo in the last 3 years. He also received travel awards (air tickets and hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubió, Takeda, Bial and Medice. The Department of Psychiatry, chaired by him, received unrestricted educational and research support from the following companies in the last 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubió. M.C. has received fees to give talks for TAKEDA and Laboratorios RUBIO. The other authors declare no competing interests.
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Supplementary information
Supplementary Information
Supplementary Figs. 1–14, Notes and Methods.
Supplementary Data 1
Forest plots of cohort-specific GWAS regression estimates for all independent significant loci. Dots indicate regression estimates; bars indicate 95% confidence intervals. The red line represents the regression estimate from the overall meta-analysis. Sample sizes for the individual cohorts are shown in Supplementary Table 2.
Supplementary Data 2
Forest plots of stratified GWAS regression estimates for all independent significant loci. Dots indicate regression estimates; bars indicate 95% confidence intervals. The red line represents the regression estimate from the overall meta-analysis.
Supplementary Data 3
Locus plots of independent significant loci. More information for these loci is available in Supplementary Table 13.
Supplementary Tables 1–20
Supplementary Tables 1–20.
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van der Laan, C.M., Ip, H.F., Schipper, M. et al. Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes. Nat Genet 57, 2427–2435 (2025). https://doi.org/10.1038/s41588-025-02295-y
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DOI: https://doi.org/10.1038/s41588-025-02295-y
