A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts
Por:
Middeldorp CM, Hammerschlag AR, Ouwens KG, Groen-Blokhuis MM, St Pourcain B, Greven CU, Pappa I, Tiesler CM, Ang W, Nolte IM, Vilor-Tejedor N, Bacelis J, Ebejer JL, Zhao H, Davies GE, Ehli EA, Evans DM, Fedko IO, Guxens M, Hottenga JJ, Hudziak JJ, Jugessur A, Kemp JP, Krapohl E, Martin NG, Murcia M, Myhre R, Ormel J, Ring SM, Standl M, Stergiakouli E, Stoltenberg C, Thiering E, Timpson NJ, Trzaskowski M, van der Most PJ, Wang C, EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, P, Nyholt DR, Medland SE, Neale B, Jacobsson B, Sunyer J, Hartman CA, Whitehouse AJ, Pennell CE, Heinrich J, Plomin R, Davey Smith G, Tiemeier H, Posthuma D and Boomsma DI
Publicada:
1 oct 2016
Ahead of Print:
5 ago 2016
Resumen:
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 x 10(-6) and 2.66 x 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.
Filiaciones:
Middeldorp CM:
Biological Psychology, Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/VU University Medical Center, Amsterdam.
Hammerschlag AR:
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
Ouwens KG:
Biological Psychology, VU University Amsterdam, and the EMGO+ Institute for Health and Care Research, VU University Medical Center
Groen-Blokhuis MM:
Biological Psychology, VU University Amsterdam, and the EMGO+ Institute for Health and Care Research, VU University Medical Center
St Pourcain B:
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
Greven CU:
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
Pappa I:
Generation R Study Group, and Pedagogical and Education Science, Erasmus University Rotterdam, The Netherlands
Tiesler CM:
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
Ang W:
School of Women's and Infants' Health, University of Western Australia, Perth
Nolte IM:
University of Groningen, University Medical Center Groningen, The Netherlands
Vilor-Tejedor N:
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Universitat Pompeu Fabra (UPF), Barcelona, and CIBER Epidemiology and Public Health (CIBERESP), Madrid
Bacelis J:
Gothenburg University, Sweden
Ebejer JL:
QIMR Berghofer Medical Research Institute, Brisbane, Australia
Zhao H:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia
Davies GE:
Avera Institute for Human Genetics, SD
Ehli EA:
Avera Institute for Human Genetics, SD
Evans DM:
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
Fedko IO:
Biological Psychology, VU University Amsterdam
Guxens M:
CREAL, UPF, CIBERESP, and Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children's Hospital, The Netherlands
Hottenga JJ:
Biological Psychology, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center
Hudziak JJ:
Vermont Center for Children, Youth and Families and College of Medicine, University of Vermont, Burlington, and Child and Adolescent Psychiatry, Erasmus Medical Center
Jugessur A:
Norwegian Institute of Public Health, Oslo
Kemp JP:
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
Krapohl E:
MRC Social, Genetic and Developmental Psychiatry Centre, King's College London
Martin NG:
QIMR Berghofer Medical Research Institute, Brisbane, Australia
:
CIBERESP, and FISABIO-Universitat Jaume I-Universitat de València Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain
Myhre R:
Norwegian Institute of Public Health, Oslo
Ormel J:
Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen
Ring SM:
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
Standl M:
Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
Stergiakouli E:
MRC IEU
Stoltenberg C:
Norwegian Institute of Public Health, Oslo
Thiering E:
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
Timpson NJ:
School of Social and Community Medicine, University of Bristol
Trzaskowski M:
MRC Social, Genetic and Developmental Psychiatry Centre, King's College London
van der Most PJ:
University of Groningen and University Medical Center Groningen
Wang C:
School of Women's and Infants' Health, University of Western Australia, Perth
Nyholt DR:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia
Medland SE:
QIMR Berghofer Medical Research Institute, Brisbane, Australia
Neale B:
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
Jacobsson B:
Obstetrics and Gynecology, Gothenburg University, and the Norwegian Institute of Public Health
Sunyer J:
CREAL, IMIM (Hospital del Mar Medical Research Institute), Barcelona, UPF, and CIBERESP
Hartman CA:
Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen
Whitehouse AJ:
Telethon Kids Institute, University of Western Australia, Perth
Pennell CE:
School of Women's and Infants' Health, University of Western Australia, Perth
Heinrich J:
Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
Plomin R:
MRC Social, Genetic and Developmental Psychiatry Centre, King's College London
Davey Smith G:
MRC IEU, and School of Social and Community Medicine
Tiemeier H:
Epidemiology, Child and Adolescent Psychiatry, and Psychiatry, Erasmus Medical Center
Posthuma D:
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
Boomsma DI:
Biological Psychology, VU University, Neuroscience Campus Amsterdam, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center
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