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Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: A meta-analysis in four European populations§

Authors

  • Cristina Sánchez-Mora,

    1. Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
    2. Psychiatric Genetics Unit, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
    3. Facultat de Biologia, Departament de Genètica, Universitat de Barcelona, Catalonia, Spain
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  • Marta Ribasés,

    1. Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
    2. Psychiatric Genetics Unit, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
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  • Miquel Casas,

    1. Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
    2. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Catalonia, Spain
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  • Mònica Bayés,

    1. Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), Catalonia, Spain
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  • Rosa Bosch,

    1. Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
    2. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Catalonia, Spain
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  • Noelia Fernàndez-Castillo,

    1. Facultat de Biologia, Departament de Genètica, Universitat de Barcelona, Catalonia, Spain
    2. CIBER Enfermedades Raras, Barcelona, Catalonia, Spain
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  • Lucas Brunso,

    1. Facultat de Biologia, Departament de Genètica, Universitat de Barcelona, Catalonia, Spain
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  • Kaya K. Jacobsen,

    1. Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    2. Department of Biomedicine, University of Bergen, Bergen, Norway
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  • Elisabeth T. Landaas,

    1. Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    2. Department of Biomedicine, University of Bergen, Bergen, Norway
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  • Astri J. Lundervold,

    1. Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
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  • Silke Gross-Lesch,

    1. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
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  • Susanne Kreiker,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany
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  • Christian P. Jacob,

    1. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
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  • Klaus-Peter Lesch,

    1. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
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  • Jan K. Buitelaar,

    1. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Martine Hoogman,

    1. Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Lambertus A.L.M. Kiemeney,

    1. Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • J.J. Sandra Kooij,

    1. PsyQ, Psycho-Medical Programs, Program Adult ADHD, The Hague, The Netherlands
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  • Eric Mick,

    1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Phil Asherson,

    1. MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, London, UK
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  • Stephen V. Faraone,

    1. Department of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York
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  • Barbara Franke,

    1. Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Andreas Reif,

    1. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
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  • Stefan Johansson,

    1. Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    2. Department of Biomedicine, University of Bergen, Bergen, Norway
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  • Jan Haavik,

    1. Department of Biomedicine, University of Bergen, Bergen, Norway
    2. Department of Psychiatry, Haukeland University Hospital, Bergen, Norway
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  • Josep Antoni Ramos-Quiroga,

    1. Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
    2. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Catalonia, Spain
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  • Bru Cormand

    Corresponding author
    1. Facultat de Biologia, Departament de Genètica, Universitat de Barcelona, Catalonia, Spain
    2. CIBER Enfermedades Raras, Barcelona, Catalonia, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain
    • Associate Professor of Genetics, Facultat de Biologia, Departament de Genètica, Universitat de Barcelona, Av. Diagonal 645, Edifici Annex, 3ª Planta, 08028 Barcelona, Spain.
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  • Conflict of interest: Netherlands: In the past 3 years, Jan K. Buitelaar has been a consultant to/member of advisory board of and/or speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, Organon/Shering Plough, UCB, Shire, Medice, and Servier. He is not an employee of any of these companies. He is not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents or royalties. Sandra Kooij has received research grants from Janssen BV en Shire, and is on the speaker's bureau of Janssen and Eli Lilly. Martine Hoogman, Lambertus Kiemeney, and Barbara Franke declare no conflicts of interest. Norway: Jan Haavik has been a consultant for Janssen Cilag and Novartis. Authors from Germany and Spain declare no conflicts of interest.

  • Barbara Franke, Andreas Reif, Stefan Johansson, Jan Haavik, Josep Antoni Ramos-Quiroga, and Bru Cormand contributed equally to this study.

  • §

    How to cite this article: Sánchez-Mora C, Ribasés M, Casas M, Bayés M, Bosch R, Fernàndez-Castillo N, Brunso L, Jacobsen KK, Landaas ET, Lundervold AJ, Gross-Lesch S, Kreiker S, Jacob CP, Lesch K-P, Buitelaar JK, Hoogman M, Kiemeney LALM, Kooij JJS, Mick E, Asherson P, Faraone SV, Franke B, Reif A, Johansson S, Haavik J, Ramos-Quiroga JA, Cormand B. 2011. Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: A meta-analysis in four European populations. Am J Med Genet Part B 156:600–612.

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4–8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple-marker meta-analysis showed a nominal association (P = 0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3′UTR VNTR-intron 8 VNTR) in the same dataset, we further tested for gene × gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene. © 2011 Wiley-Liss, Inc.

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