1. ¹Department of Child and Adolescent Psychiatry and Psychotherapy, Julius-Maximilians-University, Würzburg, Germany
2. ²Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, Julius-Maximilians-University, Würzburg, Germany
3. ³Institute of Medical Biometry and Epidemiology, Philipps-University Marburg, Marburg, Germany
4. ⁴Department of Child and Adolescent Psychiatry and Psychotherapy, Technical-University Aachen, Aachen, Germany
5. ⁵Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
6. ⁶Department of Child and Adolescent Psychiatry and Psychotherapy, District Oberpfalz, Regensburg, Regensburg, Germany
7. ⁷Department of Child and Adolescent Psychiatry and Psychotherapy, Medical University of Lübeck, Lübeck, Germany
8. ⁸Department of Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany
9. ⁹European Molecular Biology Laboratory (EMBL), Mouse Biology Programme, Monterotondo, Italy

Correspondence: Dr S Walitza, Department of Child and Adolescent Psychiatry and Psychotherapy, Julius-Maximilians-University, Füchsleinstr. 15, 97080 Würzburg, Germany. E-mail: walitza@kjp.uni-wuerzburg.de

¹⁰These authors contributed equally to this work.

Received 11 May 2005; Revised 18 July 2005; Accepted 19 July 2005; Published online 23 August 2005.

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.