Current Psychiatry Reports

, Volume 6, Issue 2, pp 143–148 | Cite as

Recent advances in the genetics of attention deficit hyperactivity disorder

  • Lindsey Kent
Article

Abstract

In the past few years, interest in the molecular genetics of attention deficit hyperactivity disorder (ADHD) has grown enormously, with many groups searching for susceptibility genes, often through large collaborative efforts facilitated by the International ADHD Genetics Consortium. Association findings for several candidate genes within the dopaminergic system, the DRD4 and DRD5 receptor genes and the dopamine transporter gene, DAT1, have been well replicated, and the first of several ongoing genome linkage scan study results have been published. Current challenges in this field are to identify the actual functional variant(s) in these genes conferring susceptibility and other genetic and environmental risk factors for ADHD.

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References and Recommended Reading

  1. 1.
    Swanson JM, Sergeant JA, Taylor E, et al.: Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998, 351:429–433.PubMedCrossRefGoogle Scholar
  2. 2.
    Meltzer H, Gatward R: Mental Health of Children and Adolescents in GB. London: The Stationery Office; 2000.Google Scholar
  3. 3.
    Thapar A, Holmes J, Poulton K, et al.: Genetic basis of attention deficit and hyperactivity. Br J Psychiatry 1999, 174:105–111.PubMedGoogle Scholar
  4. 4.
    Thapar A, Harrington R, Ross K, et al.: Does the definition of ADHD affect heritability? J Am Acad Child Adolesc Psychiatry 2000, 39:1528–1535.PubMedCrossRefGoogle Scholar
  5. 5.
    Martin N, Scourfield J, McGuffin P: Observer effects and heritability of childhood attention-deficit hyperactivity disorder symptoms. Br J Psychiatry 2002, 180:260–265.PubMedCrossRefGoogle Scholar
  6. 6.
    Simonoff E, Pickles A, Hervas A, et al.: Genetic influences on childhood hyperactivity: contrast effects imply parental rating bias, not sibling interaction. Psychol Med 1998, 28:825–837.PubMedCrossRefGoogle Scholar
  7. 7.
    West A, Langley K, Hamshere M, et al.: Evidence to suggest biased phenotypes in children with attention deficit hyperactivity disorder from completely ascertained trios. Mol Psychiatry 2002, 7:962–966.PubMedCrossRefGoogle Scholar
  8. 8.
    Silberg J, Rutter M, Meyer J, et al.: Genetic and environmental influences on the co-variation between hyperactivity and conduct disturbance in juvenile twins. J Child Psychol Psychiatry 1996, 37:803–816.PubMedCrossRefGoogle Scholar
  9. 9.
    Thapar A, Harrington R, McGuffin P: Examining the comorbidity of ADHD-related behaviors and conduct problems using a twin study design. Br J Psychiatry 2001, 179:224–229.PubMedCrossRefGoogle Scholar
  10. 10.
    Willcutt EG, Pennington BF: Psychiatric comorbidity in children and adolescents with reading disability. J Child Psychol Psychiatry 2000, 41:1039–1048.PubMedCrossRefGoogle Scholar
  11. 11.
    Willcutt EG, Pennington BF, DeFries JC: Twin study of the etiology of comorbidity between reading disability and attention-deficit/hyperactivity disorder. Am J Med Genet 2000, 96:293–301.PubMedCrossRefGoogle Scholar
  12. 12.
    Willcutt EG, Pennington BF, Smith SD, et al.: Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder. Am J Med Genet 2002, 114:260–268.PubMedCrossRefGoogle Scholar
  13. 13.
    Fisher SE, Francks C, McCracken JT, et al.: A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 2002, 70:1183–1196. This was the first published genome linkage scan of ADHD, which reported several regions of interest that may harbor ADHD susceptibility genes.PubMedCrossRefGoogle Scholar
  14. 14.
    Ogdie MN, Macphie IL, Minassian SL, et al.: A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 2003, 72:1268–1279.PubMedCrossRefGoogle Scholar
  15. 15.
    Smalley SL, Kustanovich V, Minassian SL, et al.: Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. Am J Hum Genet 2002, 71:959–963.PubMedCrossRefGoogle Scholar
  16. 16.
    Turic D, Langley K, Mills S, et al.: Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D-aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol Psychiatry 2004, in press.Google Scholar
  17. 17.
    Bakker SC, van der Meulen EM, Buitelaar JK, et al.: A wholegenome scan in 164 Dutch sib pairs with attention-deficit/ hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 2003, 72:1251–1260.PubMedCrossRefGoogle Scholar
  18. 18.
    McCracken JT, Smalley SL, McGough JJ: Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 2000, 5:531–536.PubMedCrossRefGoogle Scholar
  19. 19.
    Faraone SV, Doyle AE, Mick E, et al.: Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 2001, 158:1052–1057.PubMedCrossRefGoogle Scholar
  20. 20.
    Holmes J, Payton A, Barrett J, et al.: The role of DRD4 in children with ADHD and comorbid conduct disturbance. Am J Med Genet 2002, 114:150–153.PubMedCrossRefGoogle Scholar
  21. 21.
    Curran S, Mill J, Sham P, et al.: QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms. Am J Med Genet 2001, 105:387–393.PubMedCrossRefGoogle Scholar
  22. 22.
    Mill J, Curran S, Kent L, et al.: Association study of a SNAP-25 microsatellite and attention deficit hyperactivity disorder. Am J Med Genet 2002, 114:269–271.PubMedCrossRefGoogle Scholar
  23. 23.
    Curran S, Mill J, Tahir E, 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Kahn RS, Khoury J, Nichols WC, et al.: Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatr 2003, 143:104–110.PubMedCrossRefGoogle Scholar
  25. 25.
    Lowe N, Kirley A, Hawi Z, et al.: Joint analysis of DRD5 marker concludes association with ADHD confined to the predominantly inattentive and combined subtypes. Am J Hum Genet 2003, in press.Google Scholar
  26. 26.
    Halperin JM, Newcorn JH, Schwartz ST, et al.: Age related changes in the association between serotonin function and aggression in boys with ADHD. Biol Psychiatry 1997, 41:682–689.PubMedCrossRefGoogle Scholar
  27. 27.
    Lucki I: The spectrum of behaviors influenced by serotonin. Biol Psychiatry 1998, 44:151–162.PubMedCrossRefGoogle Scholar
  28. 28.
    Lesch KP, Bengel D, Heils A, et al.: Association of anxiety related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274:1527–1531.PubMedCrossRefGoogle Scholar
  29. 29.
    Seeger G, Schloss P, Schmidt MH: Functional polymorphism within the promoter of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry 2001, 6:235–238.PubMedCrossRefGoogle Scholar
  30. 30.
    Manor I, Eisenberg J, Tyano S, et al.: Family based association study of the serotonin transporter promoter region polymorphism (5HTTLPR) in attention deficit hyperactivity disorder. Am J Med Genet 2001, 10:91–95.CrossRefGoogle Scholar
  31. 31.
    Kent L, Doerry U, Hardy E, et al.: A family based association study of serotonin transporter polymorphisms in attention deficit hyperactivity disorder. Mol Psychiatry 2002, 7:908–912.PubMedCrossRefGoogle Scholar
  32. 32.
    Hawi Z, Dring M, Kirley A, et al.: Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample. Mol Psychiatry 2002, 7:718–725.PubMedCrossRefGoogle Scholar
  33. 33.
    Quist JF, Barr CL, Schachar R, et al.: The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry 2003, 8:98–102.PubMedCrossRefGoogle Scholar
  34. 34.
    Egan MF, Goldberg TE, Kolachana BS, et al.: Effect of COMT val Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001, 98:6917–6922. This was one of the first studies to demonstrate a relationship between genotype and neuropsychologic test performance.PubMedCrossRefGoogle Scholar
  35. 35.
    Malhotra AK, Kestler LJ, Mazzanti C, et al.: A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002, 159:652–654.PubMedCrossRefGoogle Scholar
  36. 36.
    Eisenberg J, Mei-Tal G, Steinberg A, et al.: Haplotype relative risk study of cathechol-0-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): Association of the high-enzyme activity val allele with ADHD impulsivehyperactive phenotype. Am J Med Genet 1999, 88:497–502.PubMedCrossRefGoogle Scholar
  37. 37.
    Qian Q, Wang Y, Zhou R, et al.: Family-based and case-control association studies of catechol-0-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. Am J Med Genet 2003, 118B:103–109.CrossRefGoogle Scholar
  38. 38.
    Nolan KA, Volavka J, Czobor P, et al.: Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet 2000, 10:117–124.PubMedCrossRefGoogle Scholar
  39. 39.
    Davids E, Zhang K, Tarazi FI, et al.: Animal models of attentiondeficit hyperactivity disorder. Brain Res Rev 2003, 42:1–21. This is an excellent critical review of animal models of ADHD.PubMedCrossRefGoogle Scholar
  40. 40.
    Wilson MC: Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder. Neurosci Biobehav Rev 2000, 24:51–57.PubMedCrossRefGoogle Scholar
  41. 41.
    Barr CL, Feng Y, Wigg K, et al.: Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol Psychiatry 2000, 5:405–409.PubMedCrossRefGoogle Scholar
  42. 42.
    Mill JD, Caspi A, McClay J, et al.: The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study. Mol Psychiatry 2002, 7:383–391.PubMedCrossRefGoogle Scholar
  43. 43.
    Brophy K, Hawi Z, Kirley A, et al.: Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population. Mol Psychiatry 2002, 7:913–917.PubMedCrossRefGoogle Scholar
  44. 44.
    Roman T, Szobot C, Martins S, et al.: Dopamine transporter gene and response to methylphenidate in attention-deficit/ hyperactivity disorder. Pharmacogenetics 2002, 12:497–499.PubMedCrossRefGoogle Scholar
  45. 45.
    Kirley A, Lowe N, Hawi Z, et al.: Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD. Am J Med Genet 2003, 121B:50–54.CrossRefGoogle Scholar
  46. 46.
    Hamarman S, Fossella J, Ulger C, et al.: Influence of dopamine genes on stimulant response in ADHD children. Scientific Proceedings of the 156th Annual Meeting of the American Psychiatric Association. San Francisco, CA; May 17–22, 2003.Google Scholar
  47. 47.
    Castellanos FX, Tannock R: Neuroscience of attention-deficit/ hyperactivity disorder: the search for endophenotypes. Nat Neurosci Rev 2002, 3:617–628.Google Scholar
  48. 48.
    Swanson J, Oosterlaan J, Murias M, et al.: Attention deficit/ hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. PNAS 2000, 97:4754–4759.PubMedCrossRefGoogle Scholar
  49. 49.
    Langley K, Marshall L, van den Bree M, et al.: Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. Am J Psychiatry 2004, 161:133–138.PubMedCrossRefGoogle Scholar
  50. 50.
    Rohde LA, Roman T, Szobot C, et al.: Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study. Synapse 2003, 48:87–89.PubMedCrossRefGoogle Scholar
  51. 51.
    Loo SK, Specter El, Smolen A, et al.: Functional effects of the DAT1 polymorphism on EEG measures in ADHD. J Am Acad Child Adolesc Psychiatry 2003, 42:986–993.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2004

Authors and Affiliations

  • Lindsey Kent
    • 1
  1. 1.Developmental Psychiatry SectionUniversity of CambridgeCambridgeUK

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