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:

Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT1B receptor gene in 273 nuclear families from a multi-centre sample

Molecular Psychiatry volume 7, pages 718–725 (2002)Cite this article

Abstract

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR1B and HTR2A (which encode the serotonin receptors 5-HT1B and 5-HT2A respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR1B in the total sample (for HHRR; χ2 = 7.4, P = 0.0065 and TDT; (χ2 = 6.4, P = 0.014). Analysis of HTR2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (χ2 = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.

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

Similar content being viewed by others

References

  1. Tannock R . Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research J Child Psychol Psychiat 1998; 39: 65–99

    Article  CAS  PubMed  Google Scholar 

  2. Wong AH, Buckle CE, Van Tol HH . Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 2000; 410: 183–203

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J et al. Cerebral glucose metabolism in adults with hyperactivity of childhood onset N Engl J Med 1990; 323: 1413–1415

    Article  Google Scholar 

  5. Rubia K, Overmeyer S, Taylor E, Bullmore E, Brammer M, Williams S et al. 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 1997 (May 19–23, Copenhagen, Denmark) Academic Press: New York 1997

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity Am J Hum Genet 1998; 63: 1767–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Curran S, Mill J, Tahir E, Kent L, Richards S, Gould A et al. Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples Mol Psychiatry 2001; 6: 425–428

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. Palmer CG, Bailey JN, Ramsey C, Cantwell D, Sinsheimer JS, Del'Homme M et al. No evidence of linkage or linkage disequilibrium between DAT1 and attention deficit hyperactivity disorder in a large sample Psychiatr Genet 1999; 9: 157–160

    Article  CAS  PubMed  Google Scholar 

  12. Holmes J, Payton A, Barrett JH, Hever T, Fitzpatrick H, Trumper AL et al. A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder Mol Psychiatry 2000; 5: 523–530

    Article  CAS  PubMed  Google Scholar 

  13. Faraone SV, Doyle AE, Mick E, Biederman J . Meta-analysis of the association between the 7-repeat allele of the dopamine d(4) receptor gene and attention deficit hyperactivity disorder J Am J Psychiatry 2001; 158: 1052–1057

    Article  CAS  Google Scholar 

  14. Amara S, Kuhar M . Neurotransmitter transporters: recent progress Ann Rev Neurosci 1993; 16: 73–93

    Article  CAS  PubMed  Google Scholar 

  15. Casat C, Pleasants D, Fleet J . A double-blind trial of bupropion in children with attention deficit disorder Psychopharmacol Bull 1987; 23: 120–122

    CAS  PubMed  Google Scholar 

  16. Zametkin AJ, Rapoport JL . Neurobiology of attention deficit disorder with hyperactivity: where have we come in 50 years? J Am Child Adolesc Psychiatry 1987; 26: 676–686

    Article  CAS  Google Scholar 

  17. Greenhill LL . Pharmacological treatment of attention deficit hyperactivity disorder Psychiatr Clin North Am 1992; 15: 1–27

    Article  CAS  PubMed  Google Scholar 

  18. Hechtman L . Genetic and neurobiological aspects of attention deficit hyperactivity disorder: a review J Psychiatry Neurosci 1994; 19: 193–201

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

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

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Demchyshyn L, Sunahara RK, Miller K, Teitler M, Hoffman BJ, Kennedy JL et al. A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6 Proc Natl Acad Sci USA 1992; 89: 5522–5526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Quist JF, Kennedy JL . Genetics of childhood disorders: XXIII, ADHD, part 7: the serotonin system J Am Acad Child Adolesc Psychiatry 2001; 40: 253–256

    Article  CAS  PubMed  Google Scholar 

  24. Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R et al. Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD) Mol Psychiatry 2000; 5: 537–541

    Article  CAS  PubMed  Google Scholar 

  25. O'Neill MF, Hearon-Maxwell CL, Shaw G . 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine and MK-801 but not D1 agonist C-APB Pharm Biochem Behav 1999; 63: 237–243

    Article  CAS  Google Scholar 

  26. Mill J, Curran S, Kent L, Richards S, Gould A, Virdee V et al. Attention deficit hyperactivity (ADHD) and dopamine D4 receptor gene: evidence for association but no linkage in a UK sample Mol Psychiatry 2001; 6: 440–444

    Article  CAS  PubMed  Google Scholar 

  27. Kent L, Middle F, Hawi Z, Fitzgerald M, Gill M, Feehan C et al. Nicotinic acetylcholine receptor4subunit gene polymorphism and attention hyperactivity disorder Psych Genet 2001; 11: 37–40

    Article  CAS  Google Scholar 

  28. Angold A, Costello E . A test-retest reliability study of child-reported psychiatric symptoms and diagnoses using the Child and Adolescent Psychiatric Assessment (CAPA-C) Psych Med 1995; 25: 755–762

    Article  CAS  Google Scholar 

  29. Lappalainen J, Dean M, Charbonneau L, Linnoila M, Goldman D . Mapping of the serotonin 5-HT 1D beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants Am J Med Genet 1995; 60: 157–161

    Article  CAS  PubMed  Google Scholar 

  30. Ozaki N, Rosenthal NE, Pesonen U, Lappalainen J, Feldman-Naim S, Schwartz PJ et al. Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls Biol Psychiatry 1996; 40: 1267–1272

    Article  CAS  PubMed  Google Scholar 

  31. Faraone SV, Biederman J, Monuteaux MC . Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder Genet Epidemiol 2000; 18: 1–16

    Article  CAS  PubMed  Google Scholar 

  32. Risch N, Merikangas K . The future of genetic studies of complex human diseases Science 1996; 273: 1516–1517

    Article  CAS  PubMed  Google Scholar 

  33. Frederic S, Djamel Ait A, Andree D, Marianne L, Sylvie R, Louis S et al. Enhanced aggressive behavior in mice lacking 5-HT1B receptor Science 1994; 265: 1875–1881

    Article  Google Scholar 

  34. Heisler LK, Tecott LH . A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice J Neurosci 2000; 20: RC71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rose NC, Menacker SJ, Schnur RE, Jackson L, McDonald-McGinn DM, Stump T et al. Ocular albinism in a male with del (6)(q13-q15): candidate region for autosomal recessive ocular albinism? Am J Med Genet 1992; 42: 700–705

    Article  CAS  PubMed  Google Scholar 

  36. Paterson AD, Naimark DM, Petronis A . The analysis of parental origin of alleles may detect susceptibility loci for complex disorders Hum Hered 1999; 49: 197–204

    Article  CAS  PubMed  Google Scholar 

  37. Ozaki N, Manji H, Lubierman V, Lu SJ, Lappalainen J, Rosenthal NE et al. A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization J Neurochem 1997; 68: 2186–2193

    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 (ZH and AK), and the Hyperactive and Attention Disorder (HAD) Group Ireland. The London group is supported by the MRC. SC and LK are Wellcome Trust Research Fellows. The Cardiff group is also supported by Wellcome and Action Research. Thanks are also due to Jane Holmes and Tracey Heyer who were involved in the first wave of sample collection at Manchester. We would also like to thank the families who participated in the study.

Author information

Authors and Affiliations

  1. Department of Genetics and Psychiatry, Trinity College, Dublin, Ireland

    Z Hawi, M Dring, A Kirley, D Foley, M Fitzgerald & M Gill

  2. Department of Psychiatry, Division of Neuroscience, University of Birmingham, Birmingham, UK

    L Kent & N Craddock

  3. Social, Genetic, Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK

    P Asherson, S Curran, A Gould, S Richards & D Lawson

  4. Department of Psychological Medicine, University of Wales, College of Medicine, Cardiff, Wales, UK

    H Pay, D Turic, K Langley, M Owen, M O'Donovan & A Thapar

Authors
  1. Z Hawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Dring
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Kirley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Foley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Kent
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Craddock
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Asherson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Curran
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Lawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H Pay
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Turic
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K Langley
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M O'Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A Thapar
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. M Fitzgerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z Hawi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hawi, Z., Dring, M., Kirley, A. et al. Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT1B receptor gene in 273 nuclear families from a multi-centre sample. Mol Psychiatry 7, 718–725 (2002). https://doi.org/10.1038/sj.mp.4001048

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001048

Keywords

This article is cited by

Search

Advanced search

Quick links