A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts - 22/09/16
Doi : 10.1016/j.jaac.2016.05.025
Christel M. Middeldorp, MD, PhD a, ⁎ 
, Anke R. Hammerschlag, MSc b, Klaasjan G. Ouwens, MSc c, Maria M. Groen-Blokhuis, MD, PhD c, Beate St. Pourcain, PhD d, Corina U. Greven, PhD e, Irene Pappa, MD, PhD f, Carla M.T. Tiesler, PhD g, Wei Ang, MSc h, Ilja M. Nolte, PhD i, Natalia Vilor-Tejedor, MSc j, Jonas Bacelis, MSc k, Jane L. Ebejer, PhD l, Huiying Zhao, PhD m, Gareth E. Davies, PhD n, Erik A. Ehli, PhD n, David M. Evans, PhD o, Iryna O. Fedko, MSc p, Mònica Guxens, PhD q, Jouke-Jan Hottenga, PhD r, James J. Hudziak, MD s, Astanand Jugessur, PhD t, John P. Kemp, PhD o, Eva Krapohl, MSc u, Nicholas G. Martin, PhD l, Mario Murcia, MSc v, Ronny Myhre, PhD t, Johan Ormel, PhD w, Susan M. Ring, PhD o, Marie Standl, PhD x, Evie Stergiakouli, PhD y, Camilla Stoltenberg, MD, PhD t, Elisabeth Thiering, PhD g, Nicholas J. Timpson, PhD y, z, Maciej Trzaskowski, PhD u, Peter J. van der Most, PhD aa, Carol Wang, BSc h,
, Anke R. Hammerschlag, MSc b, Klaasjan G. Ouwens, MSc c, Maria M. Groen-Blokhuis, MD, PhD c, Beate St. Pourcain, PhD d, Corina U. Greven, PhD e, Irene Pappa, MD, PhD f, Carla M.T. Tiesler, PhD g, Wei Ang, MSc h, Ilja M. Nolte, PhD i, Natalia Vilor-Tejedor, MSc j, Jonas Bacelis, MSc k, Jane L. Ebejer, PhD l, Huiying Zhao, PhD m, Gareth E. Davies, PhD n, Erik A. Ehli, PhD n, David M. Evans, PhD o, Iryna O. Fedko, MSc p, Mònica Guxens, PhD q, Jouke-Jan Hottenga, PhD r, James J. Hudziak, MD s, Astanand Jugessur, PhD t, John P. Kemp, PhD o, Eva Krapohl, MSc u, Nicholas G. Martin, PhD l, Mario Murcia, MSc v, Ronny Myhre, PhD t, Johan Ormel, PhD w, Susan M. Ring, PhD o, Marie Standl, PhD x, Evie Stergiakouli, PhD y, Camilla Stoltenberg, MD, PhD t, Elisabeth Thiering, PhD g, Nicholas J. Timpson, PhD y, z, Maciej Trzaskowski, PhD u, Peter J. van der Most, PhD aa, Carol Wang, BSc h, EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Psychiatric Genomics Consortium ADHD Working Group
Dale R. Nyholt, PhD m, Sarah E. Medland, PhD l, Benjamin Neale, PhD bb, Bo Jacobsson, MD, PhD cc, Jordi Sunyer, PhD dd, Catharina A. Hartman, PhD w, Andrew J.O. Whitehouse, PhD ee, Craig E. Pennell, MBBS, PhD h, Joachim Heinrich, PhD x, Robert Plomin, PhD u, George Davey Smith, PhD ff, Henning Tiemeier, MD, PhD gg, Danielle Posthuma, PhD hh, Dorret I. Boomsma, PhD ii a Biological Psychology, Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/VU University Medical Center, Amsterdam
b Generation R Study Group, Erasmus MC Rotterdam, the Netherlands, and Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam
c Biological Psychology, VU University Amsterdam, and the EMGO+ Institute for Health and Care Research, VU University Medical Center
d MRC Integrative Epidemiology Unit (MRC IEU), University of Bristol, UK, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands, and School of Experimental Psychology, University of Bristol
e Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Karakter, Child and Adolescent Psychiatry University Center, Radboud University Nijmegen, and MRC Social Genetic and Developmental Psychiatry Centre, King's College London
f Generation R Study Group, and Pedagogical and Education Science, Erasmus University Rotterdam, The Netherlands
g Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany and the Division of Metabolic and Nutritional Medicine, Munich, and Dr. von Hauner Children's Hospital, University of Munich Medical Center, Germany
h School of Women's and Infants' Health, University of Western Australia, Perth
i University of Groningen, University Medical Center Groningen, The Netherlands
j Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Universitat Pompeu Fabra (UPF), Barcelona, and CIBER Epidemiology and Public Health (CIBERESP), Madrid
k Gothenburg University, Sweden
l QIMR Berghofer Medical Research Institute, Brisbane, Australia
m Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia
n Avera Institute for Human Genetics, SD
o MRC IEU, School of Social and Community Medicine, and School of Social and Community Medicine, University of Bristol, and Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane
p Biological Psychology, VU University Amsterdam
q CREAL, UPF, CIBERESP, and Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children's Hospital, The Netherlands
r Biological Psychology, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center
s Vermont Center for Children, Youth and Families and College of Medicine, University of Vermont, Burlington, and Child and Adolescent Psychiatry, Erasmus Medical Center
t Norwegian Institute of Public Health, Oslo
u MRC Social, Genetic and Developmental Psychiatry Centre, King's College London
v CIBERESP, and FISABIO–Universitat Jaume I–Universitat de València Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain
w Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen
x Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
y MRC IEU
z School of Social and Community Medicine, University of Bristol
aa University of Groningen and University Medical Center Groningen
bb Program in Medical and Population Genetics and Stanley Center for Psychiatric Genetics, Broad Institute of Massachusetts Institute of Technology, Boston, Analytic and Translation Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, and Harvard University, Cambridge, MA
cc Obstetrics and Gynecology, Gothenburg University, and the Norwegian Institute of Public Health
dd CREAL, IMIM (Hospital del Mar Medical Research Institute), Barcelona, UPF, and CIBERESP
ee Telethon Kids Institute, University of Western Australia, Perth
ff MRC IEU, and School of Social and Community Medicine
gg Epidemiology, Child and Adolescent Psychiatry, and Psychiatry, Erasmus Medical Center
hh Generation R Study Group, Erasmus MC Rotterdam, the Netherlands, Child and Adolescent Psychiatry, Erasmus Medical Center, Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, and Clinical Genetics, VU University Medical Center
ii Biological Psychology, VU University, Neuroscience Campus Amsterdam, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center
∗Correspondence to Christel M. Middeldorp, MD, PhD, VU University Amsterdam, Biological Psychology, Van der Boechorststraat 1, 1081BT, Amsterdam, NetherlandsVU University AmsterdamBiological PsychologyVan der Boechorststraat 1, 1081BTAmsterdamNetherlands
Abstract |
Objective |
The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis.
Method |
Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated.
Results |
SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10−6 and 2.66 × 10−6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96.
Conclusion |
The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.
Le texte complet de cet article est disponible en PDF.Key words : GWA, SNP heritability, attention problems, ADHD symptoms, meta-analysis
Plan
| This article is discussed in an editorial by Dr. Samuele Cortese on page 839. |
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| ALSPAC: The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and they will serve as guarantors for the contents of this paper. GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. |
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| Generation R: The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Netherlands Organisation for Scientific Research (NWO), and the Ministry of Health, Welfare and Sport. H.T. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI 017.106.370). The work of A.H. and D.P. was supported by a grant from the Dutch Scientific Organisation for Scientific Research (NWO 433- 09-228 and 453-14-005). |
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| GINI/LISA: Personal and financial support by the Munich Center of Health Sciences (MCHEALTH) as part of the Ludwig-Maximilians University Munich LMU innovative is gratefully acknowledged. |
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| INMA: This study was funded by grants from the Spanish Instituto de Salud Carlos III (CB06/02/0041, G03/176, FIS PI041436, PI081151, PI041705, PI061756, PI091958, and PS09/00432, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/01007, 11/02591, 11/02038, 13/1944, 13/2032, CP11/0178 and MS13/00054), Spanish Ministry of Science and Innovation (SAF2008-00357), European Commission (ENGAGE project and grant agreement HEALTH-F4-2007- 201413, HEALTH.2010.2.4.5-1, FP7-ENV-2011 cod 282957), Fundació La Marató de TV3, Generalitat de Catalunya-CIRIT 1999SGR 00241, and Conselleria de Sanitat Generalitat Valenciana. Part of the DNA extractions and genotyping was performed at the Spanish National Genotyping Centre (CEGENBarcelona). N. Vilor-Tejedor thanks the Agència de Gestió d’Ajuts Universitaris i de Recerca - Generalitat de Catalunya for her pre-doctoral grant (2015 FI_B 00636). |
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| MoBa (Mother and Child Cohort of NIPH): This work was supported by grants from the Norwegian Research Council (FUGE 183220/S10, FRIMEDKLI-05 ES236011), Swedish Medical Society (SLS 2008-21198), Jane and Dan Olsson Foundations, and Swedish government grants to researchers in the public health service (ALFGBG-2863, ALFGBG-11522, ALFGBG-426411), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4- 2007-201413. The Norwegian Mother and Child Cohort Study was also supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1), and the Norwegian Research Council/FUGE (grant no. 151918/S10). Researchers interested in using MoBa data must obtain approval from the Scientific Management Committee of MoBa and from the Regional Committee for Medical and Health Research Ethics for access to data and biological material. Researchers are required to follow the terms of an Assistance Agreement containing a number of clauses designed to ensure protection of privacy and compliance with relevant laws. For further information, contact the principal investigator of MoBa, Per Magnus (per.magnus@fhi.no). |
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| The Netherlands Twin Register: Genetics of Mental Illness (European Research Council ERC-230374); Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMW 91210020); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); the Avera Institute, Sioux Falls, South Dakota, USA, and Grand Opportunity (grants 1RC2 MH089951 and 1RC2 MH089995). |
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| Psychiatric Genomics Consortium ADHD Working Group Members: Richard J.L. Anney, PhD, Alejandro Arias Vasquez, PhD, Philip Asherson, MD, Tobias J. Banaschewski, MD, PhD, Mònica Bayés, PhD, Joseph Biederman, MD, Jan K. Buitelaar, MD, PhD, Miguel Casas, MD, PhD, Alice Charach, MD, MSc, Bru Cormand, PhD, Jennifer Crosbie, PhD, Mark J. Daly, PhD, Alysa E. Doyle, PhD, Richard P. Ebstein, PhD, Josephine Elia, MD, Stephen V. Faraone, PhD, Barbara Franke, PhD, Christine Freitag, MD, MA, Michael Gill, MbBCh BAO, MD, MRCPsych, FTCD, Hakon Hakonarson, MD, PhD, Peter Holmans, PhD, Lindsey Kent, MD, Jonna Kuntsi, PhD, Nanda Lambregts-Rommelse, PhD, Kate Langley, PhD, Klaus-Peter Lesch, MD, Sandra K. Loo, PhD, James J. McGough, MD, Sarah E. Medland, PhD, Jobst Meyer, PhD, Eric Mick, ScD, Ana Miranda, MD, Fernando Mulas, MD, PhD, Benjamin M. Neale, PhD, Stan F. Nelson, MD, Michael C. O’Donovan, FRCPsych, PhD, Robert D. Oades, PhD, Michael J. Owen, PhD, Haukur Palmason, PhD, Josep Antoni Ramos-Quiroga, MD, PhD, Andreas Reif, MD, Tobias J. Renner, MD, Marta Ribasés, PhD, Stephan Ripke, MD, Olga Rivero, PhD, Herbert Roeyers, MD, PhD, Jasmin Romanos, MD, Marcel Romanos, MD, Aribert Rothenberger, MD, Cristina Sánchez-Mora, PhD, Russell Schachar, MD, Joseph Sergeant, PhD, Susan L. Smalley, PhD, Edmund J. S. Sonuga-Barke, PhD, Hans-Christoph Steinhausen, MD, PhD, DMSc, Anita Thapar, MBBCh, FRCPsych, PhD, FmedSci, Alexandre Todorov, PhD, Susanne Walitza, MD, Yufeng Wang, MD, PhD, Andreas Warnke, MD, PhD, Nigel Williams, PhD, Yanli Zhang-James, PhD. |
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| Dr. Middeldorp, Ms. Hammerschlag, and Mr. Ouwens contributed equally to this work. |
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| Disclosure: Dr. Hudziak has received grant or research support from the National Institutes of Health, the National Institute of Mental Health, the National Institute of Diabetes and Digestive and Kidney Disease, and the state of Vermont. His primary appointment is with the University of Vermont. He has additional appointments with Erasmus University in Rotterdam, Netherlands, Washington University School of Medicine in St. Louis, Missouri, and the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire. Drs. Middeldorp, Groen-Blokhuis, St Pourcain, Greven, Pappa, Tiesler, Nolte, Ebejer, Zhao, Davies, Ehli, Evans, Guxens, Hottenga, Jugessur, Kemp, Martin, Myhre, Ormel, Ring, Standl, Stergiakouli, Stoltenberg, Thiering, Timpson, Trzaskowski, van der Most, Nyholt, Medland, Neale, Jacobsson, Sunyer, Hartman, Whitehouse, Pennell, Heinrich, Plomin, Smith, Tiemeier, Posthuma, Boomsma, Ms. Hammerschlag, Mr. Ouwens, Mr. Ang, Ms. Vilor-Tejedor, Mr. Bacelis, Ms. Fedko, Ms. Krapohl, Mr. Murcia, and Ms. Wang report no biomedical financial interests or potential conflicts of interest. |
© 2016
American Academy of Child and Adolescent Psychiatry. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 55 - N° 10
P. 896 - octobre 2016 Retour au numéro
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