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.

  • Original Research Article
  • Published:

Dopa decarboxylase gene polymorphisms and attention deficit hyperactivity disorder (ADHD): no evidence for association in the Irish population

Abstract

Dopa decarboxylase (DDC) is an enzyme which catalyses the decarboxylation of both dopa to dopamine and L-5 hydroxytryptophan to serotonin. Both catecholamines are major neurotransmitters of the mammalian nervous system. It has been suggested that genes involved in the dopaminergic system play a primary role in predisposing to attention deficit hyperactivity disorder (ADHD). In this study, the 4-bp insertion/deletion variant mapped to the first neuronally expressed exon 1 at the dopa decarboxylase gene and two microsatellite markers flanking the gene were investigated for possible association with ADHD. Using HHRR, we observed an increased transmission (though not significant) of the 4-bp insertion (allele 1) to ADHD cases (χ2 = 2.72, P = 0.1, RR = 1.25). However marginally significant excess transmission of allele 10 (213 bp) of the 3′ microsatellite D7S2422 (0.75 cM distal to dopa decarboxylase gene) was found (χ2 = 4.2, P = 0.04, RR=1.48). Interestingly, a haplotype containing both alleles is transmitted more frequently (χ2= 5, P = 0.025). Analysing data by the sex of transmitting parent showed a greater relative risk for paternal transmission of the 4-bp insertion allele and allele 10 of the D7S2422 (RR = 1.48 and 1.63 respectively). This provides preliminary evidence that this locus or a closely mapped DNA variant may be involved in the genetic susceptibility to ADHD. However, further studies are required to either confirm or refute these observations.

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

Access options

Buy this article

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

Figure 1

Similar content being viewed by others

References

  1. Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C . Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives in psychiatrically and paediatrically referred samples Arch Gen Psychiatry 1992 49: 728–738

    Article  CAS  PubMed  Google Scholar 

  2. Biederman J, Faraone SV, Mick E, Spencer T, Wilens T, Kiely K . High risk for attention deficit hyperactivity disorder among children of parents with childhood onset of the disorder: a pilot study Am J Psychiatry 1995 152: 431–435

    Article  CAS  PubMed  Google Scholar 

  3. Silberg J, Rutter M, Meyer J, Maes H, Hewitt J, Simonoff E . Genetic and environmental influences on the covariation between hyperactivity and conduct disturbance in juvenile twins J Child Psychol Psychiatry 1996 37: 803–816

    Article  CAS  PubMed  Google Scholar 

  4. Cadoret RJ, Stewart MA . An adoption study of attention deficit/hyperactivity/aggression and their relationship to adult antisocial personality Compr Psychiatry 1991 32: 73–82

    Article  CAS  PubMed  Google Scholar 

  5. Gjone H, Stevenson J, Sundet JM . Genetic influence on parent-reported attention-related problems in a Norwegian general population twin sample J Am Acad Child Adolesc Psychiatry 1996 35: 588–596

    Article  CAS  PubMed  Google Scholar 

  6. Levy F, Hat DA, McStephen M, Wood C, Waldman I . Attention-deficit hyperactivity disorder: a category or continuum? Genetic analysis of a large-scale twin study J Am Acad Child Adolesc Psychiatry 1997 36: 737–744

    Article  CAS  PubMed  Google Scholar 

  7. Amara SG, Kuhar MJ . Neurotransmitter transporters: recent progress Annu Rev Neurosci 1993 16: 73–93

    Article  CAS  PubMed  Google Scholar 

  8. Rapport M, Denney C, DuPaul G, Gardner M . Attention deficit disorder and methylphenidate: normalization rates, clinical effectiveness, and response prediction in 76 children J Am Acad Child Adolesc Psychiatry 1994 33: 882–893

    Article  CAS  PubMed  Google Scholar 

  9. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG . Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter Nature 1996 379: 606–612

    Article  CAS  PubMed  Google Scholar 

  10. Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG . Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity Science 1999 283: 397–401

    Article  CAS  PubMed  Google Scholar 

  11. Lou HC, Henriksen L, Bruhn P . Focal cerebral dysfunction in development learning disabilities Lancet 1990 335: 8–11

    Article  CAS  PubMed  Google Scholar 

  12. Rubia K, Overmeyer S, Taylor E, Bullmore E, Brammer M, Williams S . Inhibitory control of hyperactive adolescents in fMRI. In: Toga AW, Frackowiak RSJ, Mazziotta JC (eds). Neuroimage. Third International Conference on Functional Mapping of the Human Brain (May 19–23, Copenhagen, Denmark) Academic Press: New York 1997

    Google Scholar 

  13. Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J . Cerebral glucose metabolism in adults with hyperactivity of childhood onset N Engl J Med 1990 323: 1361–1366

    Article  CAS  PubMed  Google Scholar 

  14. Ernst M, Zametkin AJ, Matochik JA, Jones P, Cohen R . DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. A (fluorine-18) fluorodopa positron emission tomographic study J Neurosci 1998 18: 5901–5907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ . Dopamine transporter density in patients with attention deficit hyperactivity disorder Lancet 1999 354: 2132–2133

    Article  CAS  PubMed  Google Scholar 

  16. Cook EH Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE . Association of attention-deficit disorder and the dopamine transporter gene Am J Hum Genet 1995 56: 993–998

    PubMed  PubMed Central  Google Scholar 

  17. Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M . Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism Mol Psychiatry 1997 2: 311–313

    Article  CAS  PubMed  Google Scholar 

  18. LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N . Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder Mol Psychiatry 1996 1: 121–124

    CAS  PubMed  Google Scholar 

  19. Daly G, Hawi Z, Fitzgerald M, Gill M . Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children Mol Psychiatry 1999 4: 192–196

    Article  CAS  PubMed  Google Scholar 

  20. Borglum AD, Bruun TG, Kjeldsen TE, Ewald H, Mors O, Kirov G . Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder Mol Psychiatry 1999 4: 545–551

    Article  CAS  PubMed  Google Scholar 

  21. Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T . Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis Biochemistry 1992 31: 2229–2238

    Article  CAS  PubMed  Google Scholar 

  22. Craig SP, Thai AL, Weber M, Craig IW . Localisation of the gene for human aromatic L-amino acid decarboxylase (DDC) to chromosome 7p13 p11 by in situ hybridisation Cytogenet Cell Genet 1992 61: 114–116

    Article  CAS  PubMed  Google Scholar 

  23. Sumi-Ichinose C, Hasegawa S, Ichinose H, Sawada H, Kobayashi K, Sakai M . Analysis of the alternative promoters that regulate tissue-specific expression of human aromatic L-amino acid decarboxylase J Neurochem 1995 64: 514–524

    Article  CAS  PubMed  Google Scholar 

  24. Chireux M, Raynal JF, Le van Thai A, Cadas H, Bernard C, Martinou I . Multiple promoters of human choline acetyltransferase and aromatic L-amino acid decarboxylase genes J Physiol Paris 1994 88: 215–227

    Article  CAS  PubMed  Google Scholar 

  25. Ward MF, Wender PH, Reimherr FW . The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder Am J Psychiatry 1993 150: 885–890

    Article  CAS  PubMed  Google Scholar 

  26. Speight G, Turic D, Austin J, Hoogendoorn B, Cardno AG, Jones L . Comparative sequencing and association studies of aromatic L-amino acid decarboxylase in schizophrenia and bipolar disorder Mol Psychiatry 2000 5: 327–331

    Article  CAS  PubMed  Google Scholar 

  27. Swirnoff AH, Milbrandt J . DNA-binding specificity of NGFI-A and related zinc finger transcription factors Mol Cell Biol 1995 15: 2275–2287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hayashida S, Yamasaki K, Asada Y, Soeda E, Niikawa N, Kishino T . Construction of a physical and transcript map flanking the imprinted MEST/PEGI region at 7q32 Genomics 2000 66: 221–225

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the generous support of the Health Research Board, Dublin, The Wellcome Trust (AK and ZH), and the Hyperactive and Attention Disorder (HAD) Group Ireland. We would also like to thank the families who participated in the study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Z Hawi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hawi, Z., Foley, D., Kirley, A. et al. Dopa decarboxylase gene polymorphisms and attention deficit hyperactivity disorder (ADHD): no evidence for association in the Irish population. Mol Psychiatry 6, 420–424 (2001). https://doi.org/10.1038/sj.mp.4000903

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000903

Keywords

This article is cited by

Search

Quick links