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; Merete Nordentoft; Ole Mors; David M Hougaard; Preben Bo Mortensen; Mark J Daly; Stephen V Faraone; Hreinn Stefansson; Panos Roussos; Barbara Franke; Thomas Werge; Benjamin M Neale; Kari Stefansson; Anders D Børglum; ADHD Working Group of the Psychiatric Genomics 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, Merete Nordentoft, Ole Mors, David M Hougaard, Preben Bo Mortensen, Mark J Daly, Stephen V Faraone, Hreinn Stefansson, Panos Roussos, Barbara Franke, Thomas Werge, Benjamin M Neale, Kari Stefansson, Anders D Børglum^*, ADHD Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › 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
Journal	Nature Genetics
Volume	55
Issue	2
Pages (from-to)	198-208
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-022-01285-8
Publication status	Published - Feb 2023

Keywords

Attention Deficit Disorder with Hyperactivity/genetics
Brain
Cognition
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans

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10.1038/s41588-022-01285-8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914347/pdf/nihms-1943028.pdf

1 Comment/debate/letter to the editor

Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains
ADHD Working Group of the Psychiatric Genomics Consortium, Apr 2023, In: Nature Genetics. 55, 4, p. 730 1 p.
Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Comment/debate/letter to the editor › Research › peer-review

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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., ... ADHD Working Group of the Psychiatric Genomics 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{cb41090c56dc431fa0562100e0538177,

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.",

keywords = "Attention Deficit Disorder with Hyperactivity/genetics, Brain, Cognition, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans",

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 Merete Nordentoft and Ole Mors and Hougaard, {David M} and Mortensen, {Preben Bo} and Daly, {Mark J} and Faraone, {Stephen V} and Hreinn Stefansson and Panos Roussos and Barbara Franke and Thomas Werge and Neale, {Benjamin M} and Kari Stefansson and B{\o}rglum, {Anders D} and {ADHD Working Group of the Psychiatric Genomics Consortium}",

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

language = "English",

volume = "55",

pages = "198--208",

journal = "Nature Genetics",

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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, Nordentoft, M, Mors, O, Hougaard, DM, Mortensen, PB, Daly, MJ, Faraone, SV, Stefansson, H, Roussos, P, Franke, B, Werge, T, Neale, BM, Stefansson, K, Børglum, AD & ADHD Working Group of the Psychiatric Genomics 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

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. / Demontis, Ditte; Walters, G Bragi; Athanasiadis, Georgios et al.
In: Nature Genetics, Vol. 55, No. 2, 02.2023, p. 198-208.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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 - Nordentoft, Merete

AU - Mors, Ole

AU - Hougaard, David M

AU - Mortensen, Preben Bo

AU - Daly, Mark J

AU - Faraone, Stephen V

AU - Stefansson, Hreinn

AU - Roussos, Panos

AU - Franke, Barbara

AU - Werge, Thomas

AU - Neale, Benjamin M

AU - Stefansson, Kari

AU - Børglum, Anders D

AU - ADHD Working Group of the Psychiatric Genomics Consortium

PY - 2023/2

Y1 - 2023/2

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.

KW - Attention Deficit Disorder with Hyperactivity/genetics

KW - Brain

KW - Cognition

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

U2 - 10.1038/s41588-022-01285-8

DO - 10.1038/s41588-022-01285-8

M3 - Journal 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

Keywords

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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

Cite this