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

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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.

Section snippets

Cohorts

The EArly Genetics and Life course Epidemiology (EAGLE) consortium is a collaboration among several population-based birth cohorts from Europe, Australia, and the United States (http://www.wikigenes.org/e/art/e/348.html). The consortium focuses on a wide range of phenotypes in childhood.20, 21 EAGLE cohorts with ADHD symptom scores in childhood (age at measurement <13 years) were invited to participate in the meta-analysis. An overview of the nine cohorts included in the meta-analysis is

SNP-Based Heritability

The estimates of the SNP-based heritability are shown in Table 2. The estimates for the maternal ratings were 5% (not significant) for preschool SDQ and 13% (not significant) and 14% (p < .05) for preschool CBCL and school-age SDQ, respectively. For teacher ratings, an SNP-based heritability of 34% (p < .05) was observed. These results indicated that SNPs tag variants associated with various ADHD symptom scores.

SNP- and Gene-Based Meta-Analyses

The numbers of SNPs from each cohort that were included in the meta-analysis after

Discussion

The current study comprised the largest GWA analysis of continuous ADHD symptom scores in children to date. We found that common variants included in GWA studies explained variation in ADHD symptom scores assessed in the general population. The SNP heritability estimates for the various measures from the participating cohorts ranged from 0.05 to 0.34. The SNP heritability based on the results of the meta-analysis in all cohorts with a total of 17,666 children was estimated at 8%. We did not

References (70)

  • M.X. Li et al.

    GATES: a rapid and powerful gene-based association test using extended Simes procedure

    Am J Hum Genet

    (2011)
  • J. Kohroki et al.

    ASB proteins interact with Cullin5 and Rbx2 to form E3 ubiquitin ligase complexes

    FEBS Lett

    (2005)
  • K. Kan et al.

    Genetic and environmental stability in attention problems across the lifespan: evidence from the Netherlands twin register

    J Am Acad Child Adolesc Psychiatry

    (2013)
  • J. Kuntsi et al.

    Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood

    Biol Psychiatry

    (2005)
  • A. Thapar et al.

    Does the definition of ADHD affect heritability?

    J Am Acad Child Adolesc Psychiatry

    (2000)
  • Diagnostic and Statistical Manual of Mental Disorders

    (2013)
  • Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • P. Lichtenstein et al.

    The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood

    Am J Psychiatry

    (2010)
  • Z. Hawi et al.

    The molecular genetic architecture of attention deficit hyperactivity disorder

    Mol Psychiatry

    (2015)
  • Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

    Lancet

    (2013)
  • M.L. Hamshere et al.

    High loading of polygenic risk for ADHD in children with comorbid aggression

    Am J Psychiatry

    (2013)
  • M.L. Hamshere et al.

    Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia

    Br J Psychiatry

    (2013)
  • M. Trzaskowski et al.

    No genetic influence for childhood behavior problems from DNA analysis

    J Am Acad Child Adolesc Psychiatry

    (2013)
  • S.H. Lee et al.

    Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

    Nat Genet

    (2013)
  • L. Yang et al.

    Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants

    Am J Med Genet B Neuropsychiatr Genet

    (2013)
  • M.M. Groen-Blokhuis et al.

    Attention-deficit/hyperactivity disorder polygenic risk scores predict attention problems in a population-based sample of children

    J Am Acad Child Adolesc Psychiatry

    (2014)
  • H. Larsson et al.

    Childhood attention-deficit hyperactivity disorder as an extreme of a continuous trait: a quantitative genetic study of 8,500 twin pairs

    J Child Psychol Psychiatry

    (2012)
  • J. Yang et al.

    Comparing apples and oranges: equating the power of case-control and quantitative trait association studies

    Genet Epidemiol

    (2010)
  • K.S. Benke et al.

    A genome-wide association meta-analysis of preschool internalizing problems

    J Am Acad Child Adolesc Psychiatry

    (2014)
  • L. Paternoster et al.

    Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

    Nat Genet

    (2011)
  • A. Boyd et al.

    Cohort profile: the 'children of the 90s'—the index offspring of the Avon Longitudinal Study of Parents and Children

    Int J Epidemiol

    (2013)
  • A. Fraser et al.

    Cohort profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort

    Int J Epidemiol

    (2013)
  • V.W. Jaddoe et al.

    The Generation R Study: design and cohort update 2010

    Eur J Epidemiol

    (2010)
  • J. Heinrich et al.

    Allergens and endotoxin on mothers' mattresses and total immunoglobulin E in cord blood of neonates

    Eur Respir J

    (2002)
  • A. von Berg et al.

    Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study

    J Allergy Clin Immunol

    (2013)
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    This article is discussed in an editorial by Dr. Samuele Cortese on page 839.

    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.

    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).

    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.

    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).

    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 ([email protected]).

    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).

    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.

    Dr. Middeldorp, Ms. Hammerschlag, and Mr. Ouwens contributed equally to this work.

    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.

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