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Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood (childhood ADHD); two-thirds of affected individuals continue to have ADHD in adulthood (persistent ADHD), and sometimes ADHD is diagnosed in adulthood (late-diagnosed ADHD). We evaluated genetic differences among childhood (n = 14,878), persistent (n = 1,473) and late-diagnosed (n = 6,961) ADHD cases alongside 38,303 controls, and rare variant differences in 7,650 ADHD cases and 8,649 controls. We identified four genome-wide significant loci for childhood ADHD and one for late-diagnosed ADHD. We found increased polygenic scores for ADHD in persistent ADHD compared with the other two groups. Childhood ADHD had higher genetic overlap with hyperactivity and autism compared with late-diagnosed ADHD and the highest burden of rare protein-truncating variants in evolutionarily constrained genes. Late-diagnosed ADHD had a larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants. Overall, these results suggest a genetic influence on age at first ADHD diagnosis, persistence of ADHD and the different comorbidity patterns among the groups.

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Fig. 1: Genetic correlations of ADHD subgroups with major psychiatric disorders and other phenotypes.
Fig. 2: Associations of PGS with childhood, persistent and late-diagnosed ADHD.
Fig. 3: The load of rPTVs and rSYNs in ADHD subgroups.

Data availability

Summary statistics from GWAS of childhood, persistent and late-diagnosed ADHD are available at the iPSYCH website (https://ipsych.dk/en/research/downloads/). All relevant iPSYCH data are available from the authors after approval by the iPSYCH Data Access Committee and can only be accessed on the secure Danish server (GenomeDK; https://genome.au.dk) as the data are protected by Danish legislation. For data access, please contact: D.D. or A.D.B. (anders@biomed.au.dk). Correspondence and requests for materials should be addressed to D.D. (ditte@biomed.au.dk).

Code availability

No previously unreported custom computer code or algorithm were used to generate results, all software used in the study are publicly available from the Internet as described in Methods and Reporting Summary.

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Acknowledgements

D.D. was supported by the Novo Nordisk Foundation (NNF20OC0065561) and the Lundbeck Foundation (R344-2020-1060). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (grant number 602805, ‘Aggressotype’) and H2020 Program (grant number 667302, ‘CoCA’), National Institute of Mental Health (1U01MH109514-01 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 at the GenomeDK high-performance computer 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.). M.S.A. is a recipient of a Juan de la Cierva Incorporación contract from the Ministry of Science, Innovation and Universities, Spain (IJC2018-035346-I). The research leading to these results has received funding from the Instituto de Salud Carlos III (PI17/00289, PI18/01788, P19/01224 and PI20/00041) and from the Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2017SGR1461) and was cofinanced by the European Regional Development Fund. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the families in Norway who have taken part in this ongoing cohort study. L.V.R. is a recipient of a predoctoral fellowship from the Instituto de Salud Carlos III, Spain (FI18/00285). M.R. was a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023). T.Z. is funded by R37MH107649-07S1 and by the Research Council of Norway (grant number 288083).

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Contributions

V.M.R, J.D. and L.V.-R. carried out the analysis. J.G., T. Z., J.A.R.-Q., F.K.S., M.S.A., J.B.-G., M.B.-H., T.D.A., A.R., M.J.D., B.M.N., M.N., T.W., O.M., D.M.H. and P.B.M. performed sample and/or data provision and processing. D.D. and V.M.R. wrote the manuscript. D.D., V.M.R., F.K.S., A.D.B. and M.R. revised the manuscript. D.D. and V.M.R. were responsible for the study design. All authors contributed with critical revisions of the manuscript.

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Correspondence to Ditte Demontis.

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Competing interests

D.D. has received a speaker fee from Takeda. J.A.R.-Q. has been on the speaker’s bureau and/or has acted as a consultant for Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice and Rubiand Raffo in the past 3 years. He has also received travel awards (air tickets and hotel) for taking part in psychiatric meetings from Janssen-Cilag, RubiShire, Takeda, Shionogi, Bial and Medice. The Department of Psychiatry chaired by him has received unrestricted educational and research support from the following companies in the past 3 years: Janssen-Cilag, Shire, Oryzon, Roche, Psious and Rubió. The remaining authors declare no competing interests.

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Rajagopal, V.M., Duan, J., Vilar-Ribó, L. et al. Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder. Nat Genet 54, 1117–1124 (2022). https://doi.org/10.1038/s41588-022-01143-7

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