Abstract
Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84–98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.
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Data availability
Summary statistics from the ADHD GWAS meta-analysis are available for download at the PGC website (https://www.med.unc.edu/pgc/download-results/). All relevant iPSYCH data are available from the authors after approval by the iPSYCH Data Access Committee and can only be accessed on the secured Danish server (GenomeDK; https://genome.au.dk) as the data are protected by Danish legislation. For data access and correspondence, please contact D.D. (ditte@biomed.au.dk) or A.D.B. (anders@biomed.au.dk).
Code availability
No previously unreported custom computer code or algorithm was used to generate results.
Change history
01 March 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41588-023-01350-w
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Acknowledgements
We thank additional members of the ADHD working group of the PGC who are not named as coauthors under the working group banner for their contributions. We would like to thank the employees and research participants of 23andMe for making this work possible. D.D. was supported by the Novo Nordisk Foundation (NNF20OC0065561), the Lundbeck Foundation (R344-2020-1060) and the European Union’s Horizon 2020 research and innovation program under grant agreement no. 965381 (TIMESPAN). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) (1U01MH109514-01 and 1R01MH124851-01 to A.D.B.) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). Research reported in this publication was supported by the NIMH of the NIH under award number R01MH124851. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. B.F. was also supported by funding from the European Community’s Horizon 2020 Programme (H2020/2014 – 2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). B.F. also received relevant funding from the Netherlands Organization for Scientific Research for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). S.E.M. was funded by National Health and Medical Research Council grants APP1172917, APP1158125 and APP1103623. This work was supported by the Instituto de Salud Carlos III (PI19/01224, PI20/0004); by the Pla Estratègic de Recerca i Innovació en Salut, Generalitat de Catalunya (METAL-Cat; SLT006/17/287); by the Agència de Gestió d’Ajuts Universitaris i de Recerca AGAUR, Generalitat de Catalunya (2017SGR1461), Ministry of Science, Innovation and Universities (IJC2018-035346-I to M.S.A.); by the European Regional Development Fund and by ‘la Marató de TV3’ (092330/31) and the European College of Neuropsychopharmacology Network ‘ADHD across the Lifespan’ (https://www.ecnp.eu/researchinnovation/ECNP-networks/List-ECNP-Networks/). T.Z. was funded by NIH, grant no. R37MH107649-07S1 and by Research Council of Norway, NRC, Grant No. 288083. This study was also supported by the NIH, Bethesda, MD, under award numbers T32MH087004 (to K.T.), K08MH122911 (to G.V.), R01MH125246 (to P.R.) and U01MH116442 (to P.R.).
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D.D., G.B.W., G.A., R.W., K.T., L.F., G.V., J.B., B.Z., W.Z., J.D., S.H.M. and T.T.N. performed the analysis. D.D., G.B.W., J.G., T.D.A., J.D., F.K.S., J.B.-G., M.B.-H., O.O.G., G.B., K.D., G.S.H., ADHD Working Group of the PGC, iPSYCH-Broad Consortium, E.A., G.E.H., M.N., O.M., D.M.H., P.B.M., M.J.D., H.S., T.W., B.M.N., K.S. and A.D.B. performed sample and/or data provision and processing. D.D., G.B.W., K.T., G.A., G.V., J.B., H.S. and A.D.B. wrote the manuscript. D.D., G.B.W., G.A., R.W., K.T., G.V., J.B., S.D., J.M., M.R., F.K.S., D.I.B., M.S.A., N.R.M., D.H., S.E.M., T.Z., V.M.R., S.V.F., H.S., P.R., B.F., B.M.N., K.S. and A.D.B. performed core revision of the manuscript. D.D. and A.D.B. provided study direction. D.D., G.B.W., H.S., P.R., B.F., T.W., B.M.N., K.S. and A.D.B. supervised the study. All authors contributed to critical revision of the manuscript.
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B.M.N. currently serves as a member of the scientific advisory board at Deep Genomics and Neumora (previously RBNC) and as a consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. All deCODE-affiliated authors are employees of deCODE/Amgen.
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Demontis, D., Walters, G.B., Athanasiadis, G. et al. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nat Genet 55, 198–208 (2023). https://doi.org/10.1038/s41588-022-01285-8
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DOI: https://doi.org/10.1038/s41588-022-01285-8
