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Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder

Molecular Psychiatry volume 9, pages 500–509 (2004)Cite this article

Abstract

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (–1251HaeIII), D1P.6 (−800HaeIII), D1.1 (−48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.

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Acknowledgements

This work was supported by grants from The Hospital for Sick Children Research Training Committee (VLM), The Hospital for Sick Children Psychiatric Endowment Fund (CLB), and the Canadian Institutes of Health Research MT14336 and MOP14334 (CLB).

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Authors and Affiliations

  1. Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada

    V L Misener, P Luca, O Azeke & C L Barr

  2. Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada

    J Crosbie, R Tannock, R Schachar, A Ickowicz & C L Barr

  3. Department of Psychology, Emory University, Atlanta, GA, USA

    I Waldman

  4. Brain and Behaviour Program, The Hospital for Sick Children, Toronto, Ontario, Canada

    R Tannock, R Schachar & C L Barr

  5. Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada

    W Roberts & M Malone

  6. Department of Psychiatry, Neurogenetics Section, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    J L Kennedy

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  1. V L Misener
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  2. P Luca
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Misener, V., Luca, P., Azeke, O. et al. Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder. Mol Psychiatry 9, 500–509 (2004). https://doi.org/10.1038/sj.mp.4001440

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Keywords

  • attention-deficit/hyperactivity disorder
  • dopamine receptor D1
  • genetics
  • linkage
  • transmission/disequilibrium test

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