Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Ditte Demontis; G. Bragi Walters; Georgios Athanasiadis; Raymond Walters; Karen Therrien; Trine Tollerup Nielsen; Leila Farajzadeh; Georgios Voloudakis; Jaroslav Bendl; Biau Zeng; Wen Zhang; Jakob Grove; Thomas D. Als; Jinjie Duan; F. Kyle Satterstrom; Jonas Bybjerg-Grauholm; Marie Bækved-Hansen; Olafur O. Gudmundsson; Sigurdur H. Magnusson; Gisli Baldursson; Katrin Davidsdottir; Gyda S. Haraldsdottir; Esben Agerbo; Gabriel E. Hoffman; Søren Dalsgaard; Joanna Martin; Marta Ribasés; Dorret I. Boomsma; Maria Soler Artigas; Nina Roth Mota; Daniel Howrigan; Sarah E. Medland; Tetyana Zayats; Veera M. Rajagopal; Alexandra Havdahl; Alysa Doyle; Andreas Reif; Anita Thapar; Bru Cormand; Calwing Liao; Christie Burton; Claiton H.D. Bau; Diego Luiz Rovaris; Edmund Sonuga-Barke; Elizabeth Corfield; Eugenio Horacio Grevet; Henrik Larsson; Ian R. Gizer; Irwin Waldman; Klaus Peter Lesch; Anders D. Borglum; ADHD Working Group of the Psychiatric Genomics Consortium; iPSYCH-Broad Consortium

doi:10.1038/s41588-022-01285-8

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Ditte Demontis^*, G. Bragi Walters, Georgios Athanasiadis, Raymond Walters, Karen Therrien, Trine Tollerup Nielsen, Leila Farajzadeh, Georgios Voloudakis, Jaroslav Bendl, Biau Zeng, Wen Zhang, Jakob Grove, Thomas D. Als, Jinjie Duan, F. Kyle Satterstrom, Jonas Bybjerg-Grauholm, Marie Bækved-Hansen, Olafur O. Gudmundsson, Sigurdur H. Magnusson, Gisli BaldurssonKatrin Davidsdottir, Gyda S. Haraldsdottir, Esben Agerbo, Gabriel E. Hoffman, Søren Dalsgaard, Joanna Martin, Marta Ribasés, Dorret I. Boomsma, Maria Soler Artigas, Nina Roth Mota, Daniel Howrigan, Sarah E. Medland, Tetyana Zayats, Veera M. Rajagopal, Alexandra Havdahl, Alysa Doyle, Andreas Reif, Anita Thapar, Bru Cormand, Calwing Liao, Christie Burton, Claiton H.D. Bau, Diego Luiz Rovaris, Edmund Sonuga-Barke, Elizabeth Corfield, Eugenio Horacio Grevet, Henrik Larsson, Ian R. Gizer, Irwin Waldman, Klaus Peter Lesch, Anders D. Borglum^*, ADHD Working Group of the Psychiatric Genomics Consortium, iPSYCH-Broad Consortium

^*Corresponding author for this work

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

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.

Original language	English
Pages (from-to)	198-208
Number of pages	11
Journal	Nature Genetics
Volume	55
Issue number	2
DOIs	https://doi.org/10.1038/s41588-022-01285-8
Publication status	Published - 1 Feb 2023

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1 Erratum / corrigendum / retractions

Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains: (Nature Genetics, (2023), 55, 2, (198-208), 10.1038/s41588-022-01285-8)
Demontis, D., Walters, G. B., Athanasiadis, G., Walters, R., Therrien, K., Nielsen, T. T., Farajzadeh, L., Voloudakis, G., Bendl, J., Zeng, B., Zhang, W., Grove, J., Als, T. D., Duan, J., Satterstrom, F. K., Bybjerg-Grauholm, J., Bækved-Hansen, M., Gudmundsson, O. O., Magnusson, S. H., Baldursson, G., & 33 othersDavidsdottir, K., Haraldsdottir, G. S., Agerbo, E., Hoffman, G. E., Dalsgaard, S., Martin, J., Ribasés, M., Boomsma, D. I., Soler Artigas, M., Roth Mota, N., Howrigan, D., Medland, S. E., Zayats, T., Rajagopal, V. M., Havdahl, A., Doyle, A., Reif, A., Thapar, A., Cormand, B., Liao, C., Burton, C., Bau, C. H. D., Rovaris, D. L., Sonuga-Barke, E., Corfield, E., Grevet, E. H., Larsson, H., Gizer, I. R., Waldman, I., Lesch, K. P., Borglum, A., ADHD Working Group of the Psychiatric Genomics Consortium & iPSYCH-Broad Consortium, 1 Apr 2023, In: Nature Genetics. 55, 4, p. 730 1 p.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

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Demontis, D., Walters, G. B., Athanasiadis, G., Walters, R., Therrien, K., Nielsen, T. T., Farajzadeh, L., Voloudakis, G., Bendl, J., Zeng, B., Zhang, W., Grove, J., Als, T. D., Duan, J., Satterstrom, F. K., Bybjerg-Grauholm, J., Bækved-Hansen, M., Gudmundsson, O. O., Magnusson, S. H., ... iPSYCH-Broad Consortium (2023). Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics, 55(2), 198-208. https://doi.org/10.1038/s41588-022-01285-8

@article{a109bca765bc499c8bf86cd2af813254,

title = "Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains",

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.",

author = "Ditte Demontis and Walters, {G. Bragi} and Georgios Athanasiadis and Raymond Walters and Karen Therrien and Nielsen, {Trine Tollerup} and Leila Farajzadeh and Georgios Voloudakis and Jaroslav Bendl and Biau Zeng and Wen Zhang and Jakob Grove and Als, {Thomas D.} and Jinjie Duan and Satterstrom, {F. Kyle} and Jonas Bybjerg-Grauholm and Marie B{\ae}kved-Hansen and Gudmundsson, {Olafur O.} and Magnusson, {Sigurdur H.} and Gisli Baldursson and Katrin Davidsdottir and Haraldsdottir, {Gyda S.} and Esben Agerbo and Hoffman, {Gabriel E.} and S{\o}ren Dalsgaard and Joanna Martin and Marta Ribas{\'e}s and Boomsma, {Dorret I.} and {Soler Artigas}, Maria and {Roth Mota}, Nina and Daniel Howrigan and Medland, {Sarah E.} and Tetyana Zayats and Rajagopal, {Veera M.} and Alexandra Havdahl and Alysa Doyle and Andreas Reif and Anita Thapar and Bru Cormand and Calwing Liao and Christie Burton and Bau, {Claiton H.D.} and Rovaris, {Diego Luiz} and Edmund Sonuga-Barke and Elizabeth Corfield and Grevet, {Eugenio Horacio} and Henrik Larsson and Gizer, {Ian R.} and Irwin Waldman and Lesch, {Klaus Peter} and Borglum, {Anders D.} and {ADHD Working Group of the Psychiatric Genomics Consortium} and {iPSYCH-Broad Consortium}",

note = "Funding Information: 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. D.D. was supported by the Novo Nordisk Foundation (NNF20OC0065561), the Lundbeck Foundation (R344-2020-1060) and the European Union{\textquoteright}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{\textquoteright}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 Estrat{\`e}gic de Recerca i Innovaci{\'o} en Salut, Generalitat de Catalunya (METAL-Cat; SLT006/17/287); by the Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}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 {\textquoteleft}la Marat{\'o} de TV3{\textquoteright} (092330/31) and the European College of Neuropsychopharmacology Network {\textquoteleft}ADHD across the Lifespan{\textquoteright} ( 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.). Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = feb,

day = "1",

doi = "10.1038/s41588-022-01285-8",

language = "English",

volume = "55",

pages = "198--208",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

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Demontis, D, Walters, GB, Athanasiadis, G, Walters, R, Therrien, K, Nielsen, TT, Farajzadeh, L, Voloudakis, G, Bendl, J, Zeng, B, Zhang, W, Grove, J, Als, TD, Duan, J, Satterstrom, FK, Bybjerg-Grauholm, J, Bækved-Hansen, M, Gudmundsson, OO, Magnusson, SH, Baldursson, G, Davidsdottir, K, Haraldsdottir, GS, Agerbo, E, Hoffman, GE, Dalsgaard, S, Martin, J, Ribasés, M, Boomsma, DI, Soler Artigas, M, Roth Mota, N, Howrigan, D, Medland, SE, Zayats, T, Rajagopal, VM, Havdahl, A, Doyle, A, Reif, A, Thapar, A, Cormand, B, Liao, C, Burton, C, Bau, CHD, Rovaris, DL, Sonuga-Barke, E, Corfield, E, Grevet, EH, Larsson, H, Gizer, IR, Waldman, I, Lesch, KP, Borglum, AD, ADHD Working Group of the Psychiatric Genomics Consortium & iPSYCH-Broad Consortium 2023, 'Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains', Nature Genetics, vol. 55, no. 2, pp. 198-208. https://doi.org/10.1038/s41588-022-01285-8

TY - JOUR

T1 - Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

AU - Demontis, Ditte

AU - Walters, G. Bragi

AU - Athanasiadis, Georgios

AU - Walters, Raymond

AU - Therrien, Karen

AU - Nielsen, Trine Tollerup

AU - Farajzadeh, Leila

AU - Voloudakis, Georgios

AU - Bendl, Jaroslav

AU - Zeng, Biau

AU - Zhang, Wen

AU - Grove, Jakob

AU - Als, Thomas D.

AU - Duan, Jinjie

AU - Satterstrom, F. Kyle

AU - Bybjerg-Grauholm, Jonas

AU - Bækved-Hansen, Marie

AU - Gudmundsson, Olafur O.

AU - Magnusson, Sigurdur H.

AU - Baldursson, Gisli

AU - Davidsdottir, Katrin

AU - Haraldsdottir, Gyda S.

AU - Agerbo, Esben

AU - Hoffman, Gabriel E.

AU - Dalsgaard, Søren

AU - Martin, Joanna

AU - Ribasés, Marta

AU - Boomsma, Dorret I.

AU - Soler Artigas, Maria

AU - Roth Mota, Nina

AU - Howrigan, Daniel

AU - Medland, Sarah E.

AU - Zayats, Tetyana

AU - Rajagopal, Veera M.

AU - Havdahl, Alexandra

AU - Doyle, Alysa

AU - Reif, Andreas

AU - Thapar, Anita

AU - Cormand, Bru

AU - Liao, Calwing

AU - Burton, Christie

AU - Bau, Claiton H.D.

AU - Rovaris, Diego Luiz

AU - Sonuga-Barke, Edmund

AU - Corfield, Elizabeth

AU - Grevet, Eugenio Horacio

AU - Larsson, Henrik

AU - Gizer, Ian R.

AU - Waldman, Irwin

AU - Lesch, Klaus Peter

AU - Borglum, Anders D.

AU - ADHD Working Group of the Psychiatric Genomics Consortium

AU - iPSYCH-Broad Consortium

N1 - Funding Information: 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. 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.). Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-022-01285-8

DO - 10.1038/s41588-022-01285-8

M3 - Article

C2 - 36702997

SN - 1061-4036

VL - 55

SP - 198

EP - 208

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Abstract

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Research output

Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains: (Nature Genetics, (2023), 55, 2, (198-208), 10.1038/s41588-022-01285-8)

Cite this