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Association and linkage of allelic variants of the dopamine transporter gene in ADHD

Molecular Psychiatry volume 12, pages 923–933 (2007)Cite this article

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.

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Acknowledgements

We thank the families for their participation in this study. We thank Professor Joseé Dupuis for stimulating discussions and helpful advices concerning the LAMP method. We thank Gundula Huth for exceptional data management. The German Ministry for Education and Research (National Genome Research Net) and the German Research Foundation (DFG; KFO 125/1-1, SCHA 542/10-2, ME 1923/5-1) financially supported this study.

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  1. S Friedel and K Saar: These authors have contributed equally to this work.

Authors and Affiliations

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

    S Friedel, B G Schimmelmann, A Hinney & J Hebebrand

  2. Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany

    K Saar & N Hübner

  3. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany

    S Sauer & R Reinhardt

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

    A Dempfle, A Scherag, C Windemuth-Kieselbach & H Schäfer

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

    S Walitza, T Renner, M Romanos, C Wewetzer & A Warnke

  6. Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg (Saar), Germany

    C Freitag & C Seitz

  7. Department of Neuro-Behavioral Genetics, University of Trier, Trier, Germany

    H Palmason & J Meyer

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

    K P Lesch

  9. Department of Child and Adolescent Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany

    B Herpertz-Dahlmann & K Konrad

  10. Department of Child and Adolescent Psychiatry, Regensburg, Germany

    M Linder

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

    H Remschmidt

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  1. S Friedel
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Friedel, S., Saar, K., Sauer, S. et al. Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 12, 923–933 (2007). https://doi.org/10.1038/sj.mp.4001986

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