Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Paula Rovira; Ditte Demontis; Cristina Sanchez-Mora; Tetyana Zayats; Marieke Klein; Nina Roth Mota; Heike Weber; Iris Garcia-Martinez; Mireia Pagerols; Laura Vilar-Ribo; Lorena Arribas; Vanesa Richarte; Montserrat Corrales; Christian Fadeuilhe; Rosa Bosch; Gemma Espanol Martin; Peter Almos; Alysa E. Doyle; Eugenio Horacio Grevet; Oliver Grimm; Anne Halmoy; Martine Hoogman; Mara Hutz; Christian P. Jacob; Sarah Kittel-Schneider; Per M. Knappskog; Astri J. Lundervold; Olga Rivero; Diego Luiz Rovaris; Angelica Salatino-Oliveira; Bruna Santos da Silva; Evgeniy Svirin; Emma Sprooten; Tatyana Strekalova; Alejandro Arias-Vasquez; Edmund J. S. Sonuga-Barke; Philip Asherson; Claiton Henrique Dotto Bau; Jan K. Buitelaar; Bru Cormand; Stephen V. Faraone; Jan Haavik; Stefan E. Johansson; Jonna Kuntsi; Henrik Larsson; Klaus-Peter Lesch; Andreas Reif; Luis Augusto Rohde; Miquel Casas; Anders D. Borglum; Barbara Franke; Josep Antoni Ramos-Quiroga; Maria Soler Artigas; Marta Ribases; ADHD Working Group of the Psychiatric Genomics Consortium; 23andMe Research team

doi:10.1038/s41386-020-0664-5

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Paula Rovira, Ditte Demontis, Cristina Sanchez-Mora, Tetyana Zayats, Marieke Klein, Nina Roth Mota, Heike Weber, Iris Garcia-Martinez, Mireia Pagerols, Laura Vilar-Ribo, Lorena Arribas, Vanesa Richarte, Montserrat Corrales, Christian Fadeuilhe, Rosa Bosch, Gemma Espanol Martin, Peter Almos, Alysa E. Doyle, Eugenio Horacio Grevet, Oliver GrimmAnne Halmoy, Martine Hoogman, Mara Hutz, Christian P. Jacob, Sarah Kittel-Schneider, Per M. Knappskog, Astri J. Lundervold, Olga Rivero, Diego Luiz Rovaris, Angelica Salatino-Oliveira, Bruna Santos da Silva, Evgeniy Svirin, Emma Sprooten, Tatyana Strekalova, Alejandro Arias-Vasquez, Edmund J. S. Sonuga-Barke, Philip Asherson, Claiton Henrique Dotto Bau, Jan K. Buitelaar, Bru Cormand, Stephen V. Faraone, Jan Haavik, Stefan E. Johansson, Jonna Kuntsi, Henrik Larsson, Klaus-Peter Lesch, Andreas Reif, Luis Augusto Rohde, Miquel Casas, Anders D. Borglum, Barbara Franke, Josep Antoni Ramos-Quiroga, Maria Soler Artigas^*, Marta Ribases^*, ADHD Working Group of the Psychiatric Genomics Consortium, 23andMe Research team

^*Corresponding author for this work

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

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Original language	English
Pages (from-to)	1617-1626
Number of pages	10
Journal	Neuropsychopharmacology
Volume	45
Issue number	10
DOIs	https://doi.org/10.1038/s41386-020-0664-5
Publication status	Published - Sept 2020

Keywords

GENOME-WIDE ASSOCIATION
DEFICIT HYPERACTIVITY DISORDER
CA2+-DEPENDENT ACTIVATOR PROTEIN
LD SCORE REGRESSION
SECRETION 2
ADHD
HERITABILITY
CHILDHOOD
SYMPTOMS
METAANALYSIS

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10.1038/s41386-020-0664-5Licence: CC BY

Cite this

Rovira, P., Demontis, D., Sanchez-Mora, C., Zayats, T., Klein, M., Mota, N. R., Weber, H., Garcia-Martinez, I., Pagerols, M., Vilar-Ribo, L., Arribas, L., Richarte, V., Corrales, M., Fadeuilhe, C., Bosch, R., Martin, G. E., Almos, P., Doyle, A. E., Grevet, E. H., ... 23andMe Research team (2020). Shared genetic background between children and adults with attention deficit/hyperactivity disorder. Neuropsychopharmacology, 45(10), 1617-1626. https://doi.org/10.1038/s41386-020-0664-5

@article{40a256c22fcd4d18a8663fa4deea4a48,

title = "Shared genetic background between children and adults with attention deficit/hyperactivity disorder",

abstract = "Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.",

keywords = "GENOME-WIDE ASSOCIATION, DEFICIT HYPERACTIVITY DISORDER, CA2+-DEPENDENT ACTIVATOR PROTEIN, LD SCORE REGRESSION, SECRETION 2, ADHD, HERITABILITY, CHILDHOOD, SYMPTOMS, METAANALYSIS",

author = "Paula Rovira and Ditte Demontis and Cristina Sanchez-Mora and Tetyana Zayats and Marieke Klein and Mota, {Nina Roth} and Heike Weber and Iris Garcia-Martinez and Mireia Pagerols and Laura Vilar-Ribo and Lorena Arribas and Vanesa Richarte and Montserrat Corrales and Christian Fadeuilhe and Rosa Bosch and Martin, {Gemma Espanol} and Peter Almos and Doyle, {Alysa E.} and Grevet, {Eugenio Horacio} and Oliver Grimm and Anne Halmoy and Martine Hoogman and Mara Hutz and Jacob, {Christian P.} and Sarah Kittel-Schneider and Knappskog, {Per M.} and Lundervold, {Astri J.} and Olga Rivero and Rovaris, {Diego Luiz} and Angelica Salatino-Oliveira and {da Silva}, {Bruna Santos} and Evgeniy Svirin and Emma Sprooten and Tatyana Strekalova and Alejandro Arias-Vasquez and Sonuga-Barke, {Edmund J. S.} and Philip Asherson and Bau, {Claiton Henrique Dotto} and Buitelaar, {Jan K.} and Bru Cormand and Faraone, {Stephen V.} and Jan Haavik and Johansson, {Stefan E.} and Jonna Kuntsi and Henrik Larsson and Klaus-Peter Lesch and Andreas Reif and Rohde, {Luis Augusto} and Miquel Casas and Borglum, {Anders D.} and Barbara Franke and {Antoni Ramos-Quiroga}, Josep and {Soler Artigas}, Maria and Marta Ribases and {ADHD Working Group of the Psychiatric Genomics Consortium} and {23andMe Research team}",

note = "Funding Information: The research leading to these results has received funding from the European Community{\textquoteright}s Seventh Framework Programme (FP7/ 2007–2013) under grant agreement n° 602805 (Aggressotype) as well as from the European Union H2020 Programme (H2020/ 2014–2020) under grant agreements n° 643051 (MiND), n° 667302 (CoCA), n° 728018 (Eat2beNICE), and n° 278948 (TACTICS). The work was also supported by the ECNP Network “ADHD across the Lifespan” (https://www.ecnp.eu/research-innovation/ECNP-networks/List-ECNP-Networks/ADHD.aspx). Over the course of this investigation, PR is a recipient of a pre-doctoral fellowship from the Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain (2016FI_B 00899). The iPSYCH project is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724) and the universities, and university hospitals of Aarhus and Copenhagen. ADB and NRM{\textquoteright}s work is also supported by the EU{\textquoteright}s Horizon 2020 programme (grant no. 667302, CoCA). Data handling and analysis was supported by NIMH (1U01MH109514-01 to Michael O{\textquoteright}Donovan and ADB). CSM is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Econom{\'i}a, Industria y Competitividad, Spain (CD15/00199). K-PL and his team are supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/ A5, no. 44541416), ERA-Net NEURON/RESPOND, no. 01EW1602B, ERA-Net NEURON/DECODE, no. 01EW1902, and 5-100 Russian Academic Excellence Project. JH thanks Stiftelsen K.G. Jebsen, University of Bergen, the Western Norwegian Health Authorities (Helse Vest). HL thanks the Swedish research council. BC received financial support from the Spanish “Ministerio de Econom{\'i}a y Competitividad” (SAF2015-68341-R) and AGAUR (2017SGR738). MSA is a recipient of a contract from the Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain. MR is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023). The research leading to these results has received funding from the Instituto de Salud Carlos III (PI16/01505, PI17/00289, PI18/01788, PI19/00721 and P19/01224), and cofinanced by the European Regional Development Fund (ERDF), from the Pla estrat{\`e}gic de recerca i innovaci{\'o} en salut (PERIS); Generalitat de Catalunya (METAL-Cat; SLT006/17/287), from “la Marat{\'o} de TV3” (092330/31) and from the Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2017SGR1461). ES{\textquoteright}s work is supported by a personal Hypatia grant from the Radboud University Medical Center. MH received a Veni grant from of the Netherlands Organization for Scientific Research (NWO, grant number 91619115). The NeuroIMAGE study was supported by NIH Grant R01MH62873 (to SVF), NWO Large Investment Grant 1750102007010 (to JKB), ZonMW grant 60-60600-97-193, NWO grants 056-13-015 and 433-09-242, and matching grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and Vrije Universiteit Amsterdam. Organization for Scientific Research (NWO; grant 016-130-669). BF and MK{\textquoteright}s work is supported by the Dutch National Science Agenda (NWA) for the NeurolabNL project (grant 400-17-602). This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. BF received additional funding from a personal Vici grant of the Dutch. The authors declare no competing interests Funding Information: VR has served on the speakers for Eli Lilly, Rubio, and Shire in the last 5 years. She has received travel awards from Eli Lilly and Co. and Shire for participating in psychiatric meetings. The ADHD Program has received unrestricted educational and research support from Eli Lilly and Co., Janssen-Cilag, Shire, Rovi, Psious, and Laboratorios Rubi{\'o} in the past 2 years. MC received travel awards for taking part in psychiatric meetings from Shire. CF received travel awards for taking part in psychiatric meetings from Shire and Lundbeck. GEM received travel awards for taking part in psychiatric meetings from Shire. EJSS-B received speaker fees, consultancy, research funding, and conference support from Shire Pharma. Consultancy from Neurotech Solutions, Copenhagen University and Berhanderling, Skolerne & KU Leuven. Book royalties from OUP and Jessica Kingsley. Financial support—Arhus University and Ghent University for visiting Professorship. Editor-in-Chief JCPP—supported by a buy-out of time to University of Southampton and personal Honorarium. King{\textquoteright}s College London received payments for work conducted by PA: consultancy for Shire, Eli Lilly, Novartis, and Lundbeck; educational and/or research awards from Shire, Eli Lilly, Novartis, Vifor Pharma, GW Pharma, and QbTech; speaker at events sponsored by Shire, Eli Lilly, Janssen-Cilag, and Novartis. JKB has been in the past 3 years a consultant to/member of advisory board of and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. In the past year, SVF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, Enzymotec, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium– hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child{\textquoteright}s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults. com. JK has given talks at educational events sponsored by Medice; all funds are received by King{\textquoteright}s College London and used for studies of ADHD. HL has served as a speaker for Evolan Pharma and Shire and has received research grants from Shire; all outside the submitted work. K-PL served as a speaker for Eli Lilly and received research support from Medice, and travel support from Shire, all outside the submitted work. LAR reported receiving honoraria, serving on the speakers{\textquoteright} bureau/advisory board, and/or acting as a consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years; receiving authorship royalties from Oxford Press and ArtMed; and receiving travel awards from Shire for his participation in the 2015 WFADHD meetings and from Novartis to take part of the 2016 AACAP meeting. The ADHD and juvenile bipolar disorder outpatient programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Janssen-Cilag, Novartis, and Shire. MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. BF has received educational speaking fees from Medice and Shire. JAR-Q was on the speakers{\textquoteright} bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubi{\'o} in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubi{\'o}, Shire, Medice, and Eli-Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubi{\'o}. The other authors have nothing to disclose. All members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. Authors of the ADHD Working group of the PGC that participated in this study: Catharina A. Hartman, Ziarih Hawi, Jennifer Crosbie, Sandra Loo, Josephine Elia, Russell Schachar, Christie Burton, Ted Reichborn-Kjennerud, Aribert Rothenberger, S{\o}ren Dalsgaard, Irwin Waldman, Mark Bellgrove, Hakon Hako-narson, Johannes Hebebrand, Anke Hinney, and Robert Oades have nothing to disclose. Joseph Biederman 2019–2020: he received research support from Genentech, Headspace Inc., Lundbeck AS, Neurocentria Inc, Pfizer Pharmaceuticals, Roche TCRC Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., and Tris. He was a consultant for Akili, Avekshan, Jazz Pharma, and Shire/Takeda. Through MGH CTNI, he participated in a scientific advisory board for Supernus. Dr Biederman{\textquoteright}s program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Tobias Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker{\textquoteright}s fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. James McGough is an expert testimony for Eli Lilly; DSMB for Sunovion. Benjamin Neale is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. Ole Andreas Andreassen received speaker{\textquoteright}s honorarium from Lundbeck, and is a consultant for HealthLytix. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = sep,

doi = "10.1038/s41386-020-0664-5",

language = "English",

volume = "45",

pages = "1617--1626",

journal = "Neuropsychopharmacology",

issn = "0893-133X",

publisher = "Springer",

number = "10",

}

Rovira, P, Demontis, D, Sanchez-Mora, C, Zayats, T, Klein, M, Mota, NR, Weber, H, Garcia-Martinez, I, Pagerols, M, Vilar-Ribo, L, Arribas, L, Richarte, V, Corrales, M, Fadeuilhe, C, Bosch, R, Martin, GE, Almos, P, Doyle, AE, Grevet, EH, Grimm, O, Halmoy, A, Hoogman, M, Hutz, M, Jacob, CP, Kittel-Schneider, S, Knappskog, PM, Lundervold, AJ, Rivero, O, Rovaris, DL, Salatino-Oliveira, A, da Silva, BS, Svirin, E, Sprooten, E, Strekalova, T, Arias-Vasquez, A, Sonuga-Barke, EJS, Asherson, P, Bau, CHD, Buitelaar, JK, Cormand, B, Faraone, SV, Haavik, J, Johansson, SE, Kuntsi, J, Larsson, H, Lesch, K-P, Reif, A, Rohde, LA, Casas, M, Borglum, AD, Franke, B, Antoni Ramos-Quiroga, J, Soler Artigas, M, Ribases, M, ADHD Working Group of the Psychiatric Genomics Consortium & 23andMe Research team 2020, 'Shared genetic background between children and adults with attention deficit/hyperactivity disorder', Neuropsychopharmacology, vol. 45, no. 10, pp. 1617-1626. https://doi.org/10.1038/s41386-020-0664-5

TY - JOUR

T1 - Shared genetic background between children and adults with attention deficit/hyperactivity disorder

AU - Rovira, Paula

AU - Demontis, Ditte

AU - Sanchez-Mora, Cristina

AU - Zayats, Tetyana

AU - Klein, Marieke

AU - Mota, Nina Roth

AU - Weber, Heike

AU - Garcia-Martinez, Iris

AU - Pagerols, Mireia

AU - Vilar-Ribo, Laura

AU - Arribas, Lorena

AU - Richarte, Vanesa

AU - Corrales, Montserrat

AU - Fadeuilhe, Christian

AU - Bosch, Rosa

AU - Martin, Gemma Espanol

AU - Almos, Peter

AU - Doyle, Alysa E.

AU - Grevet, Eugenio Horacio

AU - Grimm, Oliver

AU - Halmoy, Anne

AU - Hoogman, Martine

AU - Hutz, Mara

AU - Jacob, Christian P.

AU - Kittel-Schneider, Sarah

AU - Knappskog, Per M.

AU - Lundervold, Astri J.

AU - Rivero, Olga

AU - Rovaris, Diego Luiz

AU - Salatino-Oliveira, Angelica

AU - da Silva, Bruna Santos

AU - Svirin, Evgeniy

AU - Sprooten, Emma

AU - Strekalova, Tatyana

AU - Arias-Vasquez, Alejandro

AU - Sonuga-Barke, Edmund J. S.

AU - Asherson, Philip

AU - Bau, Claiton Henrique Dotto

AU - Buitelaar, Jan K.

AU - Cormand, Bru

AU - Faraone, Stephen V.

AU - Haavik, Jan

AU - Johansson, Stefan E.

AU - Kuntsi, Jonna

AU - Larsson, Henrik

AU - Lesch, Klaus-Peter

AU - Reif, Andreas

AU - Rohde, Luis Augusto

AU - Casas, Miquel

AU - Borglum, Anders D.

AU - Franke, Barbara

AU - Antoni Ramos-Quiroga, Josep

AU - Soler Artigas, Maria

AU - Ribases, Marta

AU - ADHD Working Group of the Psychiatric Genomics Consortium

AU - 23andMe Research team

N1 - Funding Information: The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/ 2007–2013) under grant agreement n° 602805 (Aggressotype) as well as from the European Union H2020 Programme (H2020/ 2014–2020) under grant agreements n° 643051 (MiND), n° 667302 (CoCA), n° 728018 (Eat2beNICE), and n° 278948 (TACTICS). The work was also supported by the ECNP Network “ADHD across the Lifespan” (https://www.ecnp.eu/research-innovation/ECNP-networks/List-ECNP-Networks/ADHD.aspx). Over the course of this investigation, PR is a recipient of a pre-doctoral fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain (2016FI_B 00899). The iPSYCH project is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724) and the universities, and university hospitals of Aarhus and Copenhagen. ADB and NRM’s work is also supported by the EU’s Horizon 2020 programme (grant no. 667302, CoCA). Data handling and analysis was supported by NIMH (1U01MH109514-01 to Michael O’Donovan and ADB). CSM is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CD15/00199). K-PL and his team are supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/ A5, no. 44541416), ERA-Net NEURON/RESPOND, no. 01EW1602B, ERA-Net NEURON/DECODE, no. 01EW1902, and 5-100 Russian Academic Excellence Project. JH thanks Stiftelsen K.G. Jebsen, University of Bergen, the Western Norwegian Health Authorities (Helse Vest). HL thanks the Swedish research council. BC received financial support from the Spanish “Ministerio de Economía y Competitividad” (SAF2015-68341-R) and AGAUR (2017SGR738). MSA is a recipient of a contract from the Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain. MR is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023). The research leading to these results has received funding from the Instituto de Salud Carlos III (PI16/01505, PI17/00289, PI18/01788, PI19/00721 and P19/01224), and cofinanced by the European Regional Development Fund (ERDF), from the Pla estratègic de recerca i innovació en salut (PERIS); Generalitat de Catalunya (METAL-Cat; SLT006/17/287), from “la Marató de TV3” (092330/31) and from the Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2017SGR1461). ES’s work is supported by a personal Hypatia grant from the Radboud University Medical Center. MH received a Veni grant from of the Netherlands Organization for Scientific Research (NWO, grant number 91619115). The NeuroIMAGE study was supported by NIH Grant R01MH62873 (to SVF), NWO Large Investment Grant 1750102007010 (to JKB), ZonMW grant 60-60600-97-193, NWO grants 056-13-015 and 433-09-242, and matching grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and Vrije Universiteit Amsterdam. Organization for Scientific Research (NWO; grant 016-130-669). BF and MK’s work is supported by the Dutch National Science Agenda (NWA) for the NeurolabNL project (grant 400-17-602). This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. BF received additional funding from a personal Vici grant of the Dutch. The authors declare no competing interests Funding Information: VR has served on the speakers for Eli Lilly, Rubio, and Shire in the last 5 years. She has received travel awards from Eli Lilly and Co. and Shire for participating in psychiatric meetings. The ADHD Program has received unrestricted educational and research support from Eli Lilly and Co., Janssen-Cilag, Shire, Rovi, Psious, and Laboratorios Rubió in the past 2 years. MC received travel awards for taking part in psychiatric meetings from Shire. CF received travel awards for taking part in psychiatric meetings from Shire and Lundbeck. GEM received travel awards for taking part in psychiatric meetings from Shire. EJSS-B received speaker fees, consultancy, research funding, and conference support from Shire Pharma. Consultancy from Neurotech Solutions, Copenhagen University and Berhanderling, Skolerne & KU Leuven. Book royalties from OUP and Jessica Kingsley. Financial support—Arhus University and Ghent University for visiting Professorship. Editor-in-Chief JCPP—supported by a buy-out of time to University of Southampton and personal Honorarium. King’s College London received payments for work conducted by PA: consultancy for Shire, Eli Lilly, Novartis, and Lundbeck; educational and/or research awards from Shire, Eli Lilly, Novartis, Vifor Pharma, GW Pharma, and QbTech; speaker at events sponsored by Shire, Eli Lilly, Janssen-Cilag, and Novartis. JKB has been in the past 3 years a consultant to/member of advisory board of and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. In the past year, SVF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, Enzymotec, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium– hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults. com. JK has given talks at educational events sponsored by Medice; all funds are received by King’s College London and used for studies of ADHD. HL has served as a speaker for Evolan Pharma and Shire and has received research grants from Shire; all outside the submitted work. K-PL served as a speaker for Eli Lilly and received research support from Medice, and travel support from Shire, all outside the submitted work. LAR reported receiving honoraria, serving on the speakers’ bureau/advisory board, and/or acting as a consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years; receiving authorship royalties from Oxford Press and ArtMed; and receiving travel awards from Shire for his participation in the 2015 WFADHD meetings and from Novartis to take part of the 2016 AACAP meeting. The ADHD and juvenile bipolar disorder outpatient programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Janssen-Cilag, Novartis, and Shire. MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. BF has received educational speaking fees from Medice and Shire. JAR-Q was on the speakers’ bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice, and Eli-Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. The other authors have nothing to disclose. All members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. Authors of the ADHD Working group of the PGC that participated in this study: Catharina A. Hartman, Ziarih Hawi, Jennifer Crosbie, Sandra Loo, Josephine Elia, Russell Schachar, Christie Burton, Ted Reichborn-Kjennerud, Aribert Rothenberger, Søren Dalsgaard, Irwin Waldman, Mark Bellgrove, Hakon Hako-narson, Johannes Hebebrand, Anke Hinney, and Robert Oades have nothing to disclose. Joseph Biederman 2019–2020: he received research support from Genentech, Headspace Inc., Lundbeck AS, Neurocentria Inc, Pfizer Pharmaceuticals, Roche TCRC Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., and Tris. He was a consultant for Akili, Avekshan, Jazz Pharma, and Shire/Takeda. Through MGH CTNI, he participated in a scientific advisory board for Supernus. Dr Biederman’s program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Tobias Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker’s fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. James McGough is an expert testimony for Eli Lilly; DSMB for Sunovion. Benjamin Neale is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. Ole Andreas Andreassen received speaker’s honorarium from Lundbeck, and is a consultant for HealthLytix. Publisher Copyright: © 2020, The Author(s).

PY - 2020/9

Y1 - 2020/9

N2 - Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

AB - Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

KW - GENOME-WIDE ASSOCIATION

KW - DEFICIT HYPERACTIVITY DISORDER

KW - CA2+-DEPENDENT ACTIVATOR PROTEIN

KW - LD SCORE REGRESSION

KW - SECRETION 2

KW - ADHD

KW - HERITABILITY

KW - CHILDHOOD

KW - SYMPTOMS

KW - METAANALYSIS

U2 - 10.1038/s41386-020-0664-5

DO - 10.1038/s41386-020-0664-5

M3 - Article

C2 - 32279069

SN - 0893-133X

VL - 45

SP - 1617

EP - 1626

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

IS - 10

ER -

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

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