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.
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References
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.
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.
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.
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.
Cantwell DP . Classification of child and adolescent psychopathology. J Child Psychol Psychiatr 1996; 37: 3–12.
Castellanos FX, Tannock R . Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 2002; 3: 617–628.
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.
Taylor E, Sandberg S, Thorley G, Giles S . The Epidemiology of Childhood Hyperactivity. Oxford University Press: New York, 1991.
Barkley RA . Book – Attention Deficit Hyperactivity Disorder, 2nd edn, The Guildford Press: New York, 1998.
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.
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.
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.
Thapar A, Holmes J, Poulton K, Harrington R . Genetic basis of attention deficit and hyperactivity. Br J Psychiatr 1999; 174: 105–111.
Rutter M, Giller H, Hagell A . Antisocial Behavior by Young People. Cambridge University Press: New York, London, 1998.
Wallander JL . The relationship between attention problems in childhood and antisocial behavior eight years later. J Child Psychol Psychiatr 1988; 29: 53–61.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Harold GT, Conger RD . Marital conflict and adolescent distress: the role of adolescent awareness. Child Dev 1997; 68: 333–350.
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.
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.
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.
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.
Kuntsi J, Stevenson J . Psychological mechanisms in hyperactivity: II. The role of genetic factors. J Child Psychol Psychiatr 2001; 42: 211–219.
Stevenson J . Evidence for a genetic etiology in hyperactivity in children. Behav Genet 1992; 22: 337–344.
Martin N, Scourfield J, McGuffin P . Observer effects and heritability of childhood attention-deficit hyperactivity disorder symptoms. Br J Psychiatr 2002; 180: 260–265.
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.
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.
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.
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.
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.
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.
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.
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.
Zeegers M, Rijsdijk F, Sham P . Adjusting for covariates in variance components QTL linkage analysis. Behav Genet 2004; 34: 127–133.
Moffitt TE . Adolescence-limited and life-course-persistent antisocial behavior: a developmental taxonomy. Psychol Rev 1993; 100: 674–701.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Mick E, Faraone SV, Biederman J . Age-dependent expression of attention-deficit/hyperactivity disorder symptoms. Psychiatr Clin North Am 2004; 27: 215–224.
Faraone SV, Tsuang MT . Adult attention deficit hyperactivity disorder. Curr Psychiatr Rep 2001; 3: 129–130.
McGough JJ, Barkley RA . Diagnostic controversies in adult attention deficit hyperactivity disorder. Am J Psychiatr 2004; 161: 1948–1956.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1038/sj.mp.4001831
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