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Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder

Molecular Psychiatry volume 10, pages 1126–1132 (2005)Cite this article

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.

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Acknowledgements

We thank all probands for their participation. We thank C Jambor and N Steigerwald for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 581; KFO 125/1-1; SCHA 542/10-2), the Fritz Thyssen Stiftung, the European Commission (NEWMOOD LSHM-CT-2003–503474), the Bundesministerium für Bildung und Forschung (German National Genome Net 01GS0118, 01GR0460) and the Interdisziplinäres Zentrum für Klinische Forschung, Würzburg (N-3; 01KS9603).

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Author notes

  1. S Walitza, T J Renner and A Dempfle: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry and Psychotherapy, Julius-Maximilians-University, Würzburg, Germany

    S Walitza, T J Renner, Ch Wewetzer, A Halbach & A Warnke

  2. Department of Psychiatry and Psychotherapy, Clinical and Molecular Psychobiology, Julius-Maximilians-University, Würzburg, Germany

    S Walitza, T J Renner & K P Lesch

  3. Institute of Medical Biometry and Epidemiology, Philipps-University Marburg, Marburg, Germany

    A Dempfle & H Schäfer

  4. Department of Child and Adolescent Psychiatry and Psychotherapy, Technical-University Aachen, Aachen, Germany

    K Konrad & B Herpertz-Dahlmann

  5. Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany

    H Remschmidt & J Smidt

  6. Department of Child and Adolescent Psychiatry and Psychotherapy, District Oberpfalz, Regensburg, Regensburg, Germany

    M Linder & L Flierl

  7. Department of Child and Adolescent Psychiatry and Psychotherapy, Medical University of Lübeck, Lübeck, Germany

    U Knölker

  8. Department of Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany

    S Friedel & J Hebebrand

  9. European Molecular Biology Laboratory (EMBL), Mouse Biology Programme, Monterotondo, Italy

    C Gross

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  1. S Walitza
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Correspondence to S Walitza.

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Walitza, S., Renner, T., Dempfle, A. et al. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10, 1126–1132 (2005). https://doi.org/10.1038/sj.mp.4001734

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