Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Scientific Correspondence
  • Published:

Dopamine transporter haplotype and attention-deficit hyperactivity disorder

Molecular Psychiatry volume 10, pages 617–618 (2005)Cite this article

SIR—The dopamine transporter gene (DAT1 SCL6A3) is an important candidate for mediating susceptibility to attention-deficit hyperactivity disorder (ADHD), given its relevance for related behaviors, and its blockade by effective stimulant drugs. To date, most studies examined a 40 bp variable number tandem repeat (VNTR) in the 3′-untranslated region of the gene. Along with recurrent reports of preferential transmission of the 10-repeat (480 bp) allele, there are some negative reports, and a meta-analysis of 11 studies with a total of 824 informative meioses yielded a nonsignificant pooled odds ratio estimate of 1.27 (95% CI 0.99–1.63, 0.06).1A previous study that did not detect significant association with the VNTR found a haplotype consisting of the 10-repeat allele and two 3′ biallelic sites significantly associated with ADHD.2 A recent study replicated association of the VNTR with ADHD, with stronger associations observed for 3′ microsatellite marker haplotypes that include the 10-repeat allele.3 If the VNTR is a marker for an adjacent functional DAT1 variant, a linkage disequilibrium (LD) association approach may increase the sensitivity for locating association with the phenotype, and may help explain part of the variance in previous reports that examined the VNTR as a single marker. In the present study, we examined an exon 15 haplotype located in the 3′-untranslated region, consisting of the VNTR and an upstream G2319A substitution in LD,4 in a sample of ADHD triads, confirming association with the VNTR, and stronger association with the haplotype. The sample was previously described and consisted of 76 nuclear ADHD families.5 Of these, 68 trios were informative for the VNTR site, 50 trios were informative for the A2319G site, and a total of 64 trios were informative for the haplotype analysis. The extended transmission disequilibrium test6 was used to determine allelic association with individual markers, and HAPMAX (http://www.uwcm.ac.uk/uwcm/mg/download) was used for the multimarker haplotype relative risk (HRR) analysis. The DAT1 VNTR alleles showed marginally significant biased transmission to affected children (χ2 for genotype-wise TDT=9.08, df=3, P=0.028); preferential transmission was also observed for the 2319 G allele (χ2=3.97, df=1, P=0.046) (Table 1). The two sites demonstrated strong LD (D′ coefficient=1.000). Multimarker HRR analysis showed a globally significant biased transmission of haplotypes (χ2=14.56, df=5, P=0.0124).

Table 1 Association tests between DAT markers and ADHD (TDT)
Full size table

Among the individual haplotypes that contributed to the global significance of the haplotype analysis, relative risk calculation for the haplotype 11-G vs the others provided a significant protective RR of 0.69 (CI 1.09–84.48; χ2=4.097, df=1, P=0.043), although with a very small effect size (w=0.179), and haplotype 10-G vs the others provided a modest RR of 1.56 (CI 0.84–2.86). The rest of the haplotype combinations did not show any transmission differences among affected and unaffected children (Table 2).

Table 2 Family-based association test between DAT markers and ADHD (haplotypes)
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Maher BS et al. Psychiatr Genet 2002; 12: 207–215.

  2. Barr CL et al. Biol Psychiatry 2001; 49: 333–339.

  3. Hawi Z et al. Mol Psychiatry 2003; 8: 299–308.

  4. Ueno S et al. Mol Psychiatry 1999; 4: 552–557.

  5. Segman RH et al. Mol Psychiatry 2002; 7: 72–74.

  6. Sham P, Curtis D . Ann Hum Genet 1995; 59: 323–336.

  7. Greenwood TA, Kelsoe JR . Genomics 2003; 82: 511–520.

  8. Miller GM, Madras BK . Mol Psychiatry 2002; 7: 44–55.

  9. Kang AM et al. Biol Psychiatry 1999; 46: 151–160.

  10. Greenwood TA et al. Am J Med Genet 2001; 105: 145–151.

  11. Vandenbergh DJ et al. Mol Psychiatry 2000; 5: 283–292.

  12. Grunehage F et al. Mol Psychiatry 2000; 5: 275–282.

  13. Greenwood TA et al. Mol Psychiatry 2002; 7: 165–173.

  14. Khan RS et al. J Pediatr 2003; 143: 104.

Download references

Author information

Authors and Affiliations

  1. Child & Adolescent Psychiatry Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    E Galili-Weisstub, S Levy & A Meltzer

  2. Geha Psychiatric Hospital, Petah Tikva and Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    A Frisch, E Michaelovsky, A Kosov & A Weizman

  3. Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem, Israel

    V Gross-Tsur

  4. Department of Psychiatry, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    T Goltser & R H Segman

  5. Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Milan, Italy

    A Serretti & C Cusin

  6. Life Sciences Institute, The Hebrew University, Jerusalem, Israel

    A Darvasi & E Inbar

Authors
  1. E Galili-Weisstub
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Frisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Gross-Tsur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Michaelovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Kosov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Meltzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Goltser
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Serretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Cusin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Darvasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E Inbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A Weizman
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R H Segman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R H Segman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galili-Weisstub, E., Levy, S., Frisch, A. et al. Dopamine transporter haplotype and attention-deficit hyperactivity disorder. Mol Psychiatry 10, 617–618 (2005). https://doi.org/10.1038/sj.mp.4001655

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001655

This article is cited by

Search

Advanced search

Quick links