Functional Studies of Candidate Genes Involved in Attention-deficit–Hyperactivity Disorder

Thegna Mavroconstanti, Ingeborg Winge, Jeffrey A McKinney, Per M Knappskog, Jan Haavik
European Psychiatric Review, 2010;3(1):44-46
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Abstract

Attention-deficit–hyperactivity disorder (ADHD) is a common and highly heritable childhood psychiatric disorder that often persists into adulthood. Genetic studies have identified various chromosomal loci and candidate genes that may be associated with this condition. Recently, genome-wide association studies (GWAS) have also been used to search for ADHD susceptibility loci and genes. Thus, the number of genetic variants reported to be potentially involved in ADHD is rapidly increasing. However, molecular studies and identification of possible pathogenetic mechanisms are still rare and not systematically performed. In this article we illustrate how functional studies can provide insight into disease mechanisms and new possibilities for intervention. Furthermore, we briefly review some key experimental approaches and recent findings on selected ADHD candidate genes, and provide suggestions for future research.
Keywords
Attention-deficit–hyperacticity disorder (ADHD), candidate genes, single nucleotide polymorphisms (SNPs), functional studies, DRD4, DAT1, TPH2
Disclosure Jan Haavik has received honoraria as a speaker for Janssen-Cilag and Novartis. The remaining authors have no conflicts of interest to declare.
Received: October 24, 2009 Accepted January 15, 2010
Correspondence: Thegna Mavroconstanti, Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway. E: Thegna.Mavroconstanti@biomed.uib.no
Genetics of Attention-deficit–Hyperactivity Disorder

The heritability of childhood attention-deficit–hyperactivity disorder (ADHD) has been estimated to be approximately 76%, and typical prevalence estimates are around 5.3% for school-age children and 1–4% for adults.1 It is a genetically and phenotypically complex condition that is highly co-morbid with other psychiatric disorders. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria, three ADHD subtypes are defined – a predominantly inattentive, a predominantly hyperactive–impulsive and a combined subtype – but it is unclear to what extent these subtypes correspond to biologically distinct disorders.2

Using linkage studies, multiple chromosomal regions have been implicated in ADHD. However, most linkage signals have been weak and difficult to reproduce, and have generally not led to a definitive identification of unequivocal ADHD susceptibility genes. On the basis of pharmacological relevance, anatomical and chromosomal location and biological function, candidate gene association studies have been extensively performed in ADHD. Most studies have focused on genes that code for proteins involved in the dopamine, noradrenaline and serotonin pathways. The dopamine and noradrenaline transporters (DAT and NET) constitute the primary targets of drugs used to treat ADHD, and serotonin pathways may also be affected.3

Early studies identified associations between ADHD and polymorphisms within the dopamine D4 receptor gene (DRD4),4 the dopamine D5 gene (DRD5),5 the dopamine transporter 1 gene (DAT1),5 the dopamine beta hydroxylase gene (DBH),5 the catechol-O-methyltransferase gene (COMT),6 the NET gene,7 a promoter region of the serotonin transporter gene (5-HTT)8 and synaptosome-associated protein 25kDa (SNAP25).9 However, few of these findings have been successfully replicated. For instance, lack of association of DRD4, DRD5 and DAT1 with ADHD has also been reported.10

References:
  1. Franke B, Neale BM, Hum Genet, 2009;126(1):13–50.
  2. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), Fourth edition, Washington, DC: American Psychiatric Association, 2000;78–85.
  3. Gainetdinov RR, Wetsel WC, Jones SR, et al., Science, 1999;283(5400):397–401.
  4. LaHoste GJ, Swanson JM, Wigal SB, et al., Mol Psychiatry, 1996;1(2):121–4.
  5. Hawi Z, Lowe N, Kirley A, et al., Mol Psychiatry, 2003;8(3):299–308.
  6. Eisenberg J, Mei-Tal G, Steinberg A, et al., Am J Med Genet, 1999;88(5):497–502.
  7. Kim CH, Hahn MK, Joung Y, et al., Proc Natl Acad Sci U S A, 2006;103(50):19164–9.
  8. Retz W, Thome J, Blocher D, et al., Neurosci Lett, 2002;319(3):133–6.
  9. Barr CL, Feng Y, Wigg K, et al., Mol Psychiatry, 2000;5(4):405–9.
  10. Bakker SC, van der Meulen EM, Oteman N, et al., Am J Med Genet B Neuropsychiatr Genet, 2005;132B(1):50–52.
  11. Hirschhorn JN, Daly MJ, Nat Rev Genet, 2005;6(2):95–108.
  12. Lasky-Su J, Neale BM, Franke B, et al., Am J Med Genet B Neuropsychiatr Genet, 2008;147B(8):1345–54.
  13. Lesch KP, Timmesfeld N, Renner TJ, et al., J Neural Transm, 2008;115(11):1573–85.
  14. Bakker SC, van der Meulen EM, Buitelaar JK, et al., Am J Hum Genet, 2003;72(5):1251–60.
  15. Ogdie MN, Macphie IL, Minassian SL, et al., Am J Hum Genet, 2003;72(5):1268–79.
  16. Kruglyak L, Nickerson DA, Nat Genet, 2001;27(3):234–6.
  17. Seaman MI, Fisher JB, Chang F, et al., Am J Med Genet, 1999;88(6):705–9.
  18. D’Souza UM, Russ C, Tahir E, et al., Biol Psychiatry, 2004;56(9):691–7.
  19. VanNess SH, Owens MJ, Kilts CD, BMC Genet, 2005;6:55.
  20. Fuke S, Suo S, Takahashi N, et al., Pharmacogenomics J, 2001;1(2):152–6.
  21. Mill J, Asherson P, Craig I, et al., BMC Genet, 2005;6(1):3.
  22. Heinz A, Goldman D, Jones DW, et al., Neuropsychopharmacology, 2000;22(2):133–9.
  23. Jacobsen LK, Staley JK, Zoghbi SS, et al., Am J Psychiatry, 2000;157(10):1700–3.
  24. Mazei-Robison MS, Bowton E, Holy M, et al., J Neurosci, 2008;28(28):7040–46.
  25. McKinney J, Johansson S, Halmoy A, et al., Mol Psychiatry, 2008;13(4):365–7.
  26. McKinney JA, Turel B, Winge I, et al., Hum Mutat, 2009;30(5):787–94.
  27. Hosak L, Eur Psychiatry, 2007;22(5):276–81.
  28. Lachman HM, Papolos DF, Saito T, et al., Pharmacogenetics, 1996;6(3):243–50.
  29. Nackley AG, Shabalina SA, Tchivileva IE, et al., Science, 2006;314(5807):1930–33.
  30. Halleland H, Lundervold AJ, Halmoy A, et al., Am J Med Genet B Neuropsychiatr Genet, 2009;150B(3):403–10.
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