Meta-Analysis

. 2016 Oct;55(10):896-905.e6.

doi: 10.1016/j.jaac.2016.05.025. Epub 2016 Aug 5.

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Christel M Middeldorp^#¹, Anke R Hammerschlag^#¹, Klaasjan G Ouwens^#¹, Maria M Groen-Blokhuis¹, Beate St Pourcain¹, Corina U Greven¹, Irene Pappa¹, Carla M T Tiesler¹, Wei Ang¹, Ilja M Nolte¹, Natalia Vilor-Tejedor¹, Jonas Bacelis¹, Jane L Ebejer¹, Huiying Zhao¹, Gareth E Davies¹, Erik A Ehli¹, David M Evans¹, Iryna O Fedko¹, Mònica Guxens¹, Jouke-Jan Hottenga¹, James J Hudziak¹, Astanand Jugessur¹, John P Kemp¹, Eva Krapohl¹, Nicholas G Martin¹, Mario Murcia¹, Ronny Myhre¹, Johan Ormel¹, Susan M Ring¹, Marie Standl¹, Evie Stergiakouli¹, Camilla Stoltenberg¹, Elisabeth Thiering¹, Nicholas J Timpson¹, Maciej Trzaskowski¹, Peter J van der Most¹, Carol Wang¹; EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Psychiatric Genomics Consortium ADHD Working Group; Dale R Nyholt¹, Sarah E Medland¹, Benjamin Neale¹, Bo Jacobsson¹, Jordi Sunyer¹, Catharina A Hartman¹, Andrew J O Whitehouse¹, Craig E Pennell¹, Joachim Heinrich¹, Robert Plomin¹, George Davey Smith¹, Henning Tiemeier¹, Danielle Posthuma¹, Dorret I Boomsma¹

Affiliations

Affiliation

¹ Dr. Middeldorp is with Biological Psychology, Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/ VU University Medical Center, Amsterdam. Ms. Hammerschlag is with the 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. Mr. Ouwens and Dr. Groen-Blokhuis are with Biological Psychology, VU University Amsterdam, and the EMGO+ Institute for Health and Care Research, VU University Medical Center. Dr. St. Pourcain is with 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. Dr. Greven is with 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. Dr. Pappa is with Generation R Study Group, and Pedagogical and Education Science, Erasmus University Rotterdam, The Netherlands. Drs. Tiesler and Thiering are with 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. Mr. Ang, Ms. Wang, and Dr. Pennell are with School of Women's and Infants' Health, University of Western Australia, Perth. Dr. Nolte is with University of Groningen, University Medical Center Groningen, The Netherlands. Ms. Vilor-Tejedor is with Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Universitat Pompeu Fabra (UPF), Barcelona, and CIBER Epidemiology and Public Health (CIBERESP), Madrid. Mr. Bacelis is with Gothenburg University, Sweden. Drs. Ebejer, Martin, and Medland are with QIMR Berghofer Medical Research Institute, Brisbane, Australia. Drs. Zhao and Nyholt are with Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia. Drs. Davies and Ehli are with Avera Institute for Human Genetics, SD. Drs. Evans, Kemp, and Ring are with 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. Ms. Fedko is with Biological Psychology, VU University Amsterdam. Dr. Guxens is with CREAL, UPF, CIBERESP, and Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children´s Hospital, The Netherlands. Dr. Hottenga is with Biological Psychology, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center. Dr. Hudziak is with Vermont Center for Children, Youth and Families and College of Medicine, University of Vermont, Burlington, and Child and Adolescent Psychiatry, Erasmus Medical Center. Drs. Jugessur, Myhre, and Stoltenberg are with the Norwegian Institute of Public Health, Oslo. Ms. Krapohl and Drs. Trzaskowski and Plomin are with MRC Social, Genetic and Developmental Psychiatry Centre, King's College London. Mr. Murcia is with CIBERESP, and FISABIO-Universitat Jaume I-Universitat de València Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain. Drs. Ormel and Hartman are with the Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen. Drs. Standl and Heinrich are with Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Drs. Stergiakouli and Timpson are with MRC IEU; Dr. Timpson is also with School of Social and Community Medicine, University of Bristol. Dr. van der Most is with University of Groningen and University Medical Center Groningen. Dr. Neale is with 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. Dr. Jacobsson is with Obstetrics and Gynecology, Gothenburg University, and the Norwegian Institute of Public Health. Dr. Sunyer is with CREAL, IMIM (Hospital del Mar Medical Research Institute), Barcelona, UPF, and CIBERESP. Dr. Whitehouse is with Telethon Kids Institute, University of Western Australia, Perth. Dr. Davey Smith is with MRC IEU, and School of Social and Community Medicine. Dr. Tiemeier is with Epidemiology, Child and Adolescent Psychiatry, and Psychiatry, Erasmus Medical Center. Dr. Posthuma is with the 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. Dr. Boomsma is with Biological Psychology, VU University, Neuroscience Campus Amsterdam, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center.

^# Contributed equally.

PMID: 27663945
PMCID: PMC5068552
DOI: 10.1016/j.jaac.2016.05.025

Meta-Analysis

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Christel M Middeldorp et al. J Am Acad Child Adolesc Psychiatry. 2016 Oct.

. 2016 Oct;55(10):896-905.e6.

doi: 10.1016/j.jaac.2016.05.025. Epub 2016 Aug 5.

Authors

Affiliation

¹ Dr. Middeldorp is with Biological Psychology, Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/ VU University Medical Center, Amsterdam. Ms. Hammerschlag is with the 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. Mr. Ouwens and Dr. Groen-Blokhuis are with Biological Psychology, VU University Amsterdam, and the EMGO+ Institute for Health and Care Research, VU University Medical Center. Dr. St. Pourcain is with 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. Dr. Greven is with 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. Dr. Pappa is with Generation R Study Group, and Pedagogical and Education Science, Erasmus University Rotterdam, The Netherlands. Drs. Tiesler and Thiering are with 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. Mr. Ang, Ms. Wang, and Dr. Pennell are with School of Women's and Infants' Health, University of Western Australia, Perth. Dr. Nolte is with University of Groningen, University Medical Center Groningen, The Netherlands. Ms. Vilor-Tejedor is with Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Universitat Pompeu Fabra (UPF), Barcelona, and CIBER Epidemiology and Public Health (CIBERESP), Madrid. Mr. Bacelis is with Gothenburg University, Sweden. Drs. Ebejer, Martin, and Medland are with QIMR Berghofer Medical Research Institute, Brisbane, Australia. Drs. Zhao and Nyholt are with Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia. Drs. Davies and Ehli are with Avera Institute for Human Genetics, SD. Drs. Evans, Kemp, and Ring are with 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. Ms. Fedko is with Biological Psychology, VU University Amsterdam. Dr. Guxens is with CREAL, UPF, CIBERESP, and Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children´s Hospital, The Netherlands. Dr. Hottenga is with Biological Psychology, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center. Dr. Hudziak is with Vermont Center for Children, Youth and Families and College of Medicine, University of Vermont, Burlington, and Child and Adolescent Psychiatry, Erasmus Medical Center. Drs. Jugessur, Myhre, and Stoltenberg are with the Norwegian Institute of Public Health, Oslo. Ms. Krapohl and Drs. Trzaskowski and Plomin are with MRC Social, Genetic and Developmental Psychiatry Centre, King's College London. Mr. Murcia is with CIBERESP, and FISABIO-Universitat Jaume I-Universitat de València Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain. Drs. Ormel and Hartman are with the Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen. Drs. Standl and Heinrich are with Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Drs. Stergiakouli and Timpson are with MRC IEU; Dr. Timpson is also with School of Social and Community Medicine, University of Bristol. Dr. van der Most is with University of Groningen and University Medical Center Groningen. Dr. Neale is with 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. Dr. Jacobsson is with Obstetrics and Gynecology, Gothenburg University, and the Norwegian Institute of Public Health. Dr. Sunyer is with CREAL, IMIM (Hospital del Mar Medical Research Institute), Barcelona, UPF, and CIBERESP. Dr. Whitehouse is with Telethon Kids Institute, University of Western Australia, Perth. Dr. Davey Smith is with MRC IEU, and School of Social and Community Medicine. Dr. Tiemeier is with Epidemiology, Child and Adolescent Psychiatry, and Psychiatry, Erasmus Medical Center. Dr. Posthuma is with the 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. Dr. Boomsma is with Biological Psychology, VU University, Neuroscience Campus Amsterdam, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center.

^# Contributed equally.

PMID: 27663945
PMCID: PMC5068552
DOI: 10.1016/j.jaac.2016.05.025

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.

Keywords: ADHD symptoms; GWA; SNP heritability; attention problems; meta-analysis.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Figure 1**
QQ-plot of all meta-analysis results based on at least 10,000 individuals.

**Figure 2**
Manhattan plot of the meta-analysis results based on at least 10,000 individuals.

See this image and copyright information in PMC

References

1. Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics. 2012;9:490–499. - PMC - PubMed
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text rev ed. Washington, DC: Author; 2000.
1. Lichtenstein P, Carlstrom E, Rastam M, Gillberg C, Anckarsater H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry. 2010;167:1357–1363. - PubMed
1. Hawi Z, Cummins TD, Tong J, et al. The molecular genetic architecture of attention deficit hyperactivity disorder. Mol Psychiatry. 2015;20:289–297. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Affiliation

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Authors

Affiliation

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials