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.

  • Feature Review
  • Published:

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies

Abstract

It is well established that attention deficit hyperactivity disorder (ADHD) is a familial and highly heritable disorder. Consequently, much effort is being directed towards searching for specific susceptibility genes. There is a growing trend, across the field of complex disease genetics, towards undertaking secondary analyses based on refined phenotypic definitions and in testing whether specific susceptibility genes modify the phenotypic presentation of the disorder in question. It is crucial that good, empirically derived arguments are made before undertaking multiple analyses on different phenotype refinements. In this review article, we consider the evidence from genetic epidemiological studies as well as key clinical studies that provide guidance on examining the ADHD phenotype for the purpose of molecular genetic studies. Specifically, findings on categorical versus dimensional conceptualisations of ADHD, reporter effects, comorbidity, ADHD subtypes and persistence are reviewed. Current evidence suggests that for the purpose of identifying susceptibility genes for ADHD, parent and teachers should be used as informants and that focusing on the clinical diagnosis of ADHD is useful. There is also good empirical support in favour of examining antisocial behaviour in ADHD. Genetic studies of dimensional ADHD are useful for other complementary purposes.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatr 2005; 57: 1313–1323.

    Article  CAS  Google Scholar 

  2. Thapar A, O'Donovan M, Owen MJ . The genetics of attention deficit hyperactivity disorder. Hum Mol Genet 2005 Oct 15;14 Spec No. 2:R275-82.

    Article  CAS  Google Scholar 

  3. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 418: 426–430.

    Article  CAS  Google Scholar 

  4. Hamshere ML, Williams N, Norton N, Williams H, Cardno A, Zammit S et al. Genome-wide significant linkage in schizophrenia conditioning on occurrence of depressive episodes. J Med Genet 2005; October 14: Epub ahead of print.

  5. Cantwell DP . Classification of child and adolescent psychopathology. J Child Psychol Psychiatr 1996; 37: 3–12.

    Article  CAS  Google Scholar 

  6. Castellanos FX, Tannock R . Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 2002; 3: 617–628.

    Article  CAS  Google Scholar 

  7. Doyle AE, Willcutt EG, Seidman LJ, Biederman J, Chouinard VA, Silva J et al. Attention-deficit/hyperactivity disorder endophenotypes. Biol Psychiatr 2005; 57: 1324–1335.

    Article  CAS  Google Scholar 

  8. Taylor E, Sandberg S, Thorley G, Giles S . The Epidemiology of Childhood Hyperactivity. Oxford University Press: New York, 1991.

    Google Scholar 

  9. Barkley RA . Book – Attention Deficit Hyperactivity Disorder, 2nd edn, The Guildford Press: New York, 1998.

    Google Scholar 

  10. Goodman R, Stevenson J . A twin study of hyperactivity – II. The aetiological role of genes, family relationships and perinatal adversity. J Child Psychol Psychiatr 1989; 30: 691–709.

    Article  CAS  Google Scholar 

  11. Thapar A, Harrington R, Ross K, McGuffin P . Does the definition of ADHD affect heritability? J Am Acad Child Adolesc Psychiatr 2000; 39: 1528–1536.

    Article  CAS  Google Scholar 

  12. Sherman DK, McGue MK, Iacono WG . Twin concordance for attention deficit hyperactivity disorder: a comparison of teachers' and mothers' reports. Am J Psychiatr 1997; 154: 532–535.

    Article  CAS  Google Scholar 

  13. Thapar A, Holmes J, Poulton K, Harrington R . Genetic basis of attention deficit and hyperactivity. Br J Psychiatr 1999; 174: 105–111.

    Article  CAS  Google Scholar 

  14. Rutter M, Giller H, Hagell A . Antisocial Behavior by Young People. Cambridge University Press: New York, London, 1998.

    Google Scholar 

  15. Wallander JL . The relationship between attention problems in childhood and antisocial behavior eight years later. J Child Psychol Psychiatr 1988; 29: 53–61.

    Article  CAS  Google Scholar 

  16. Fergusson DM, Horwood LJ . Predictive validity of categorically and dimensionally scored measures of disruptive childhood behaviors. J Am Acad Child Adolesc Psychiatr 1995; 34: 477–485; discussion 85–87.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Thapar A, Fowler T, Rice F, Scourfield J, van den Bree M, Thomas H et al. Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring. Am J Psychiatr 2003; 160: 1985–1989.

    Article  Google Scholar 

  19. Langley K, Rice F, van den Bree MB, Thapar A . Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behavior. A review. Minerva Pediatr 2005; 57: 359–371.

    CAS  PubMed  Google Scholar 

  20. Mill J, Xu X, Ronald A, Curran S, Price T, Knight J et al. Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B. Am J Med Genet B Neuropsychiatr Genet 2005; 133: 68–73.

    Article  Google Scholar 

  21. Payton A, Holmes J, Barrett JH, Sham P, Harrington R, McGuffin P et al. Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins. Psychiatr Res 2001; 105: 273–278.

    Article  CAS  Google Scholar 

  22. Cornish KM, Manly T, Savage R, Swanson J, Morisano D, Butler N et al. Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Mol Psychiatr 2005; 10: 686–698.

    Article  CAS  Google Scholar 

  23. Curran S, Purcell S, Craig I, Asherson P, Sham P . The serotonin transporter gene as a QTL for ADHD. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 42–47.

    Article  Google Scholar 

  24. Pickles A, Angold A . Natural categories or fundamental dimensions: on carving nature at the joints and the rearticulation of psychopathology. Dev Psychopathol 2003; 15: 529–551.

    Article  Google Scholar 

  25. Harold GT, Conger RD . Marital conflict and adolescent distress: the role of adolescent awareness. Child Dev 1997; 68: 333–350.

    CAS  PubMed  Google Scholar 

  26. Thapar A, Hervas A, McGuffin P . Childhood hyperactivity scores are highly heritable and show sibling competition effects: twin study evidence. Behav Genet 1995; 25: 537–544.

    Article  CAS  Google Scholar 

  27. Simonoff E, Pickles A, Hervas A, Silberg JL, Rutter M, Eaves L . Genetic influences on childhood hyperactivity: contrast effects imply parental rating bias, not sibling interaction. Psychol Med 1998; 28: 825–837.

    Article  CAS  Google Scholar 

  28. Nadder TS, Rutter M, Silberg JL, Maes HH, Eaves LJ . Genetic effects on the variation and covariation of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder/conduct disorder (Odd/CD) symptomatologies across informant and occasion of measurement. Psychol Med 2002; 32: 39–53.

    Article  CAS  Google Scholar 

  29. Ho TP, Luk ES, Leung PW, Taylor E, Lieh-Mak F, Bacon-Shone J . Situational versus pervasive hyperactivity in a community sample. Psychol Med 1996; 26: 309–321.

    Article  CAS  Google Scholar 

  30. Kuntsi J, Stevenson J . Psychological mechanisms in hyperactivity: II. The role of genetic factors. J Child Psychol Psychiatr 2001; 42: 211–219.

    Article  CAS  Google Scholar 

  31. Stevenson J . Evidence for a genetic etiology in hyperactivity in children. Behav Genet 1992; 22: 337–344.

    Article  CAS  Google Scholar 

  32. Martin N, Scourfield J, McGuffin P . Observer effects and heritability of childhood attention-deficit hyperactivity disorder symptoms. Br J Psychiatr 2002; 180: 260–265.

    Article  Google Scholar 

  33. Barkley RA, Fischer M, Smallish L, Fletcher K . The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol 2002; 111: 279–289.

    Article  Google Scholar 

  34. Nadder TS, Silberg JL, Rutter M, Maes HH, Eaves LJ . Comparison of multiple measures of ADHD symptomatology: a multivariate genetic analysis. J Child Psychol Psychiatr 2001; 42: 475–486.

    Article  CAS  Google Scholar 

  35. Costello EJ, Loeber R, Stouthamer-Loeber M . Pervasive and situational hyperactivity – confounding effect of informant: a research note. J Child Psychol Psychiatr 1991; 32: 367–376.

    Article  CAS  Google Scholar 

  36. Mannuzza S, Klein RG, Klein DF, Bessler A, Shrout P . Accuracy of adult recall of childhood attention deficit hyperactivity disorder. Am J Psychiatr 2002; 159: 1882–1888.

    Article  Google Scholar 

  37. Curran S, Rijsdijk F, Martin N, Marusic K, Asherson P, Taylor E et al. CHIP: Defining a dimension of the vulnerability to attention deficit hyperactivity disorder (ADHD) using sibling and individual data of children in a community-based sample. Am J Med Genet B Neuropsychiatr Genet 2003; 119: 86–97.

    Article  Google Scholar 

  38. Boomsma DI, Dolan CV . A comparison of power to detect a QTL in sib-pair data using multivariate phenotypes, mean phenotypes, and factor scores. Behav Genet 1998; 28: 329–340.

    Article  CAS  Google Scholar 

  39. Hauser ER, Hsu FC, Daley D, Olson JM, Rampersaud E, Lin JP et al. Effects of covariates: a summary of Group 5 contributions. Genet Epidemiol 2003; 25(Suppl 1): S43–S49.

    Article  Google Scholar 

  40. Thapar A, Langley K, Fowler T, Rice F, Turic D, Whittinger N et al. Catechol O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatr 2005; 62: 1275–1278.

    Article  CAS  Google Scholar 

  41. Zeegers M, Rijsdijk F, Sham P . Adjusting for covariates in variance components QTL linkage analysis. Behav Genet 2004; 34: 127–133.

    Article  Google Scholar 

  42. Moffitt TE . Adolescence-limited and life-course-persistent antisocial behavior: a developmental taxonomy. Psychol Rev 1993; 100: 674–701.

    Article  CAS  Google Scholar 

  43. 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  Google Scholar 

  44. Thapar A, Harrington R, McGuffin P . Examining the comorbidity of ADHD-related behaviors and conduct problems using a twin study design. Br J Psychiatr 2001; 179: 224–229.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Holmes J, Payton A, Barrett J, Harrington R, McGuffin P, Owen M et al. Association of DRD4 in children with ADHD and comorbid conduct problems. Am J Med Genet 2002; 114: 150–153.

    Article  Google Scholar 

  47. Kirley A, Lowe N, Mullins C, McCarron M, Daly G, Waldman I et al. Phenotype studies of the DRD4 gene polymorphisms in ADHD: association with oppositional defiant disorder and positive family history. Am J Med Genet B Neuropsychiatr Genet 2004; 131: 38–42.

    Article  Google Scholar 

  48. 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.

    Article  CAS  Google Scholar 

  49. Willcutt EG, Pennington BF, Smith SD, Cardon LR, Gayan J, Knopik VS 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.

    Article  Google Scholar 

  50. Loo SK, Fisher SE, Francks C, Ogdie MN, MacPhie IL, Yang M et al. Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects. Mol Psychiatr 2004; 9: 485–493.

    Article  CAS  Google Scholar 

  51. Faraone SV, Biederman J, Friedman D . Validity of DSM-IV subtypes of attention-deficit/hyperactivity disorder: a family study perspective. J Am Acad Child Adolesc Psychiatr 2000; 39: 300–307.

    Article  CAS  Google Scholar 

  52. Smalley SL, McGough JJ, Del'Homme M, NewDelman J, Gordon E, Kim T et al. Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatr 2000; 39: 1135–1143.

    Article  CAS  Google Scholar 

  53. Todd RD, Rasmussen ER, Neuman RJ, Reich W, Hudziak JJ, Bucholz KK et al. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am J Psychiatr 2001; 158: 1891–1898.

    Article  CAS  Google Scholar 

  54. Sherman DK, Iacono WG, McGue MK . Attention-deficit hyperactivity disorder dimensions: a twin study of inattention and impulsivity-hyperactivity. J Am Acad Child Adolesc Psychiatr 1997; 36: 745–753.

    Article  CAS  Google Scholar 

  55. Hudziak JJ, Heath AC, Madden PF, Reich W, Bucholz KK, Slutske W et al. Latent class and factor analysis of DSM-IV ADHD: a twin study of female adolescents. J Am Acad Child Adolesc Psychiatr 1998; 37: 848–857.

    Article  CAS  Google Scholar 

  56. Rasmussen ER, Neuman RJ, Heath AC, Levy F, Hay DA, Todd RD . Familial clustering of latent class and DSM-IV defined attention-deficit/hyperactivity disorder (ADHD) subtypes. J Child Psychol Psychiatr 2004; 45: 589–598.

    Article  Google Scholar 

  57. Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ et al. Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes. Am J Hum Genet 2004; 74: 348–356.

    Article  CAS  Google Scholar 

  58. 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  Google Scholar 

  59. Todd RD, Sitdhiraksa N, Reich W, Ji TH, Joyner CA, Heath AC et al. Discrimination of DSM-IV and latent class attention-deficit/hyperactivity disorder subtypes by educational and cognitive performance in a population-based sample of child and adolescent twins. J Am Acad Child Adolesc Psychiatr 2002; 41: 820–828.

    Article  Google Scholar 

  60. Neuman RJ, Heath A, Reich W, Bucholz KK, Madden PAF, Sun L et al. Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins. J Child Psychol Psychiatr 2001; 42: 933–942.

    Article  CAS  Google Scholar 

  61. Rasmussen ER, Neuman RJ, Heath AC, Levy F, Hay DA, Todd RD . Replication of the latent class structure of Attention-Deficit/Hyperactivity Disorder (ADHD) subtypes in a sample of Australian twins. J Child Psychol Psychiatr 2002; 43: 1018–1028.

    Article  Google Scholar 

  62. Todd RD, Lobos EA, Sun LW, Neuman RJ . Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit/hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems. Mol Psychiatr 2003; 8: 103–108.

    Article  CAS  Google Scholar 

  63. Mick E, Faraone SV, Biederman J . Age-dependent expression of attention-deficit/hyperactivity disorder symptoms. Psychiatr Clin North Am 2004; 27: 215–224.

    Article  Google Scholar 

  64. Faraone SV, Tsuang MT . Adult attention deficit hyperactivity disorder. Curr Psychiatr Rep 2001; 3: 129–130.

    Article  CAS  Google Scholar 

  65. McGough JJ, Barkley RA . Diagnostic controversies in adult attention deficit hyperactivity disorder. Am J Psychiatr 2004; 161: 1948–1956.

    Article  Google Scholar 

  66. Inkster B, Muglia P, Jain U, Kennedy JL . Linkage disequilibrium analysis of the dopamine beta-hydroxylase gene in persistent attention deficit hyperactivity disorder. Psychiatr Genet 2004; 14: 117–120.

    Article  Google Scholar 

  67. De Luca V, Muglia P, Jain U, Kennedy JL . No evidence of linkage or association between the norepinephrine transporter (NET) gene MnlI polymorphism and adult ADHD. Am J Med Genet B Neuropsychiatr Genet 2004; 124: 38–40.

    Article  Google Scholar 

  68. Larsson JO, Larsson H, Lichtenstein P . Genetic and environmental contributions to stability and change of ADHD symptoms between 8 and 13 years of age: a longitudinal twin study. J Am Acad Child Adolesc Psychiatr 2004; 43: 1267–1275.

    Article  Google Scholar 

  69. Price TS, Simonoff E, Asherson P, Curran S, Kuntsi J, Waldman I et al. Continuity and change in preschool ADHD symptoms: longitudinal genetic analysis with contrast effects. Behav Genet 2005; 35: 121–132.

    Article  Google Scholar 

  70. Rietveld MJ, Hudziak JJ, Bartels M, van Beijsterveldt CE, Boomsma DI . Heritability of attention problems in children: longitudinal results from a study of twins, age 3–12. J Child Psychol Psychiatr 2004; 45: 577–588.

    Article  CAS  Google Scholar 

  71. El-Faddagh M, Laucht M, Maras A, Vohringer L, Schmidt MH . Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age. J Neural Transm 2004; 111: 883–889.

    Article  CAS  Google Scholar 

  72. Pankratz N, Mukhopadhyay N, Huang S, Foroud T, Kirkwood SC . Identification of genes for complex disease using longitudinal phenotypes. BMC Genet 2003; 4(Suppl 1): S58.

    Article  Google Scholar 

  73. North KE, Martin LJ, Dyer T, Comuzzie AG, Williams JT . HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q. BMC Genet 2003; 4(Suppl 1): S98.

    Article  Google Scholar 

Download references

Acknowledgements

KL is funded by the Wellcome Trust (Value in Person Award). Part of this paper is based upon a presentation made by AT at the EUNETHYDIS meeting, Santorini, Greece, September 2003. We thank Professor Jim Stevenson for his suggestion to develop this paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Thapar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thapar, A., Langley, K., O'Donovan, M. et al. Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies. Mol Psychiatry 11, 714–720 (2006). https://doi.org/10.1038/sj.mp.4001831

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001831

Keywords

This article is cited by

Search

Quick links