1. ¹Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany
2. ²Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany
3. ³Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin-Dahlem, Germany
4. ⁴Institute of Medical Biometry and Epidemiology, Philipps-University, Marburg, Germany
5. ⁵Department of Child and Adolescent Psychiatry and Psychotherapy, Julius-Maximilians-University, Würzburg, Germany
6. ⁶Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg (Saar), Germany
7. ⁷Department of Neuro-Behavioral Genetics, University of Trier, Trier, Germany
8. ⁸Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, Julius-Maximilians-University, Würzburg, Germany
9. ⁹Department of Child and Adolescent Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany
10. ¹⁰Department of Child and Adolescent Psychiatry, Regensburg, Germany
11. ¹¹Department of Child and Adolescent Psychiatry, Philipps-University, Marburg, Germany

Correspondence: Professor J Hebebrand, Department of Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany. E-mail: Johannes.Hebebrand@uni-duisburg-essen.de

¹²These authors have contributed equally to this work.

Received 2 October 2006; Revised 16 January 2007; Accepted 4 February 2007; Published online 10 April 2007.

Abstract

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.