Aetiology

The aetiology of attention-deficit hyperactivity disorder (ADHD), or hyperkinetic disorder (HKD), is under continuous investigation, although there is now a growing body of evidence for the interplay between multiple genetic1-7 and environmental risk factors8-17 risk factors that affect the neurobiological basis18-21 of the disorder.

Preliminary evidence suggests that genetics play a role in individual susceptibility to ADHD,1-7 with the estimated heritability of ADHD estimated to be 76% of the population,1 and the involvement of specific candidate genes reported.3,5 There is also evidence for a genetic component associated with the persistence of ADHD into adulthood.5 Preliminary evidence suggests that individual genetic differences may contribute to the variability in response to ADHD medication,22 although this is an area which requires further research.

The neurobiological component of ADHD has received much attention in recent years. Evidence exists for the association between ADHD and possible structural,18,24-26 functional,21,27 electrical activity19 and chemical20,28 correlates in various regions of the brain in children, adolescents and adults with ADHD.29-33

It is likely that the aetiology of ADHD results from complex interactions between groups of susceptible genes and environmental influences;34 considerable evidence for the involvement of environmental risk factors in the development of ADHD has been reported:

  • Premature birth, low birth weight and prenatal tobacco/alcohol exposure8,10-12
  • Environmental contaminants13,14
  • Socioeconomic adversity8-10,15,16
  • Specific gene–environment interactions16,17

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  1. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313-1323.
  2. Sprich S, Biederman J, Crawford MH, et al. Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2000; 39: 1432-1437.
  3. Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 2009; 126: 51-90.
  4. Larsson H, Chang Z, D'Onofrio BM, et al. The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychol Med 2013; 1-7.
  5. Lesch KP, Timmesfeld N, Renner TJ, et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 2008; 115: 1573-1585.
  6. Levy F, Hay DA, McStephen M, et al. Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry 1997; 36: 737-744.
  7. Larsson H, Asherson P, Chang Z, et al. Genetic and environmental influences on adult attention deficit hyperactivity disorder symptoms: a large Swedish population-based study of twins. Psychol Med 2013; 43: 197-207.
  8. Galera C, Cote SM, Bouvard MP, et al. Early risk factors for hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years. Arch Gen Psychiatry 2011; 68: 1267-1275.
  9. Heinonen K, Raikkonen K, Pesonen AK, et al. Behavioural symptoms of attention deficit/hyperactivity disorder in preterm and term children born small and appropriate for gestational age: a longitudinal study. BMC Pediatr 2010; 10: 91.
  10. Langley K, Holmans PA, van den Bree MB, et al. Effects of low birth weight, maternal smoking in pregnancy and social class on the phenotypic manifestation of Attention Deficit Hyperactivity Disorder and associated antisocial behaviour: investigation in a clinical sample. BMC Psychiatry 2007; 7: 26.
  11. D’Onofrio BM, Van Hulle CA, Waldman ID, et al. Causal inferences regarding prenatal alcohol exposure and childhood externalizing problems. Arch Gen Psychiatry 2007; 64: 1296-1304.
  12. Kotimaa AJ, Moilanen I, Taanila A, et al. Maternal smoking and hyperactivity in 8-year-old children. J Am Acad Child Adolesc Psychiatry 2003; 42: 826-833.
  13. Surkan PJ, Zhang A, Trachtenberg F, et al. Neuropsychological function in children with blood lead levels <10 microg/dL. Neurotoxicology 2007; 28: 1170-1177.
  14. Chiodo LM, Jacobson SW, Jacobson JL. Neurodevelopmental effects of postnatal lead exposure at very low levels. Neurotoxicol Teratol 2004; 26: 359-371.
  15. Hjern A, Weitoft GR, Lindblad F. Social adversity predicts ADHD-medication in school children--a national cohort study. Acta Paediatr 2010; 99: 920-924.
  16. Grizenko N, Fortier ME, Zadorozny C, et al. Maternal Stress during Pregnancy, ADHD Symptomatology in Children and Genotype: Gene-Environment Interaction. J Can Acad Child Adolesc Psychiatry 2012; 21: 9-15.
  17. Martel MM, Nikolas M, Jernigan K, et al. The dopamine receptor D4 gene (DRD4) moderates family environmental effects on ADHD. J Abnorm Child Psychol 2011; 39: 1-10.
  18. Nakao T, Radua J, Rubia K, et al. Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry 2011; 168: 1154-1163.
  19. Quintana H, Snyder SM, Purnell W, et al. Comparison of a standard psychiatric evaluation to rating scales and EEG in the differential diagnosis of attention-deficit/hyperactivity disorder. Psychiatry Res 2007; 152: 211-222.
  20. Economidou D, Theobald DE, Robbins TW, et al. Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens. Neuropsychopharmacology 2012; 37: 2057-2066.
  21. Cortese S, Kelly C, Chabernaud C, et al. Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry 2012; 169: 1038-1055.
  22. Froehlich TE, Epstein JN, Nick TG, et al. Pharmacogenetic predictors of methylphenidate dose-response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2011; 50: 1129-1139.
  23. Ivanov I, Bansal R, Hao X, et al. Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 2010; 167: 397-408.
  24. Pavuluri MN, Yang S, Kamineni K, et al. Diffusion tensor imaging study of white matter fiber tracts in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. Biol Psychiatry 2009; 65: 586-593.
  25. Davenport ND, Karatekin C, White T, et al. Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia. Psychiatry Res 2010; 181: 193-198.
  26. Kobel M, Bechtel N, Specht K, et al. Structural and functional imaging approaches in attention deficit/hyperactivity disorder: does the temporal lobe play a key role? Psychiatry Res 2010; 183: 230-236.
  27. Dickstein SG, Bannon K, Castellanos FX, et al. The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry 2006; 47: 1051-1062.
  28. Volkow ND, Wang GJ, Kollins SH, et al. Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA 2009; 302: 1084-1091.
  29. Proal E, Reiss PT, Klein RG, et al. Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatry 2011; 68: 1122-1134.
  30. Hart H, Radua J, Nakao T, et al. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry 2013; 70: 185-198.
  31. Hoogman M, Rijpkema M, Janss L, et al. Current self-reported symptoms of attention deficit/hyperactivity disorder are associated with total brain volume in healthy adults. PLoS One 2012; 7: e31273.
  32. Makris N, Biederman J, Valera EM, et al. Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cereb Cortex 2007; 17: 1364-1375.
  33. Makris N, Liang L, Biederman J, et al. Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naive Adults. J Atten Disord 2013.
  34. Waldman ID, Rhee SH. Behavioral and molecular genetic studies in: Sandberg S, ed. Hyperactivity and Attention Disorders of childhood. 2nd edition. New York: Wiley, 2002: 290-335.

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