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Attention-Deficit/Hyperactivity Disorder Genomics: Update for Clinicians

  • Attention-Deficit Disorder (R Bussing, Section Editor)
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Abstract

Attention deficit, hyperactivity disorder (ADHD) is familial and highly heritable. Several candidate genes involved in neurotransmission have been identified, however these confer minimal risk, suggesting that for the most part, ADHD is not caused by single common genetic variants. Advances in genotyping enabling investigation at the level of the genome have led to the discovery of rare structural variants suggesting that ADHD is a genomic disorder, with potentially thousands of variants, and common neuronal pathways disrupted by numerous rare variants resulting in similar ADHD phenotypes. Heritability studies in humans also indicate the importance of epigenetic factors, and animal studies are deciphering some of the processes that confer risk during gestation and throughout the post-natal period. These and future discoveries will lead to improved diagnosis, individualized treatment, cures, and prevention. These advances also highlight ethical and legal issues requiring management and interpretation of genetic data and ensuring privacy and protection from misuse.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C, et al. Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry. 1992;49(9):728–38.

    Article  PubMed  CAS  Google Scholar 

  2. Lombroso PJ, Pauls DL, Leckman JF. Genetic mechanisms in childhood psychiatric disorders. J Am Acad Child Adolesc Psychiatry. 1994;33(7):921–38.

    Article  PubMed  CAS  Google Scholar 

  3. Faraone SV, Biederman J, Keenan K, Tsuang MT. A family-genetic study of girls with DSM-III attention deficit disorder. Am J Psychiatry. 1991;148(1):112–7.

    PubMed  CAS  Google Scholar 

  4. Faraone SV, Biederman J, Chen WJ, Milberger S, Warburton R, Tsuang MT. Genetic heterogeneity in attention-deficit hyperactivity disorder (ADHD): gender, psychiatric comorbidity, and maternal ADHD. J Abnorm Psychol. 1995;104(2):334–45.

    Article  PubMed  CAS  Google Scholar 

  5. Faraone SV, Biederman J, Milberger S. An exploratory study of ADHD among second-degree relatives of ADHD children. Biol Psychiatry. 1994;35(6):398–402.

    Article  PubMed  CAS  Google Scholar 

  6. Sprich S, Biederman J, Crawford MH, Mundy E, Faraone SV. Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2000;39(11):1432–7.

    Article  PubMed  CAS  Google Scholar 

  7. Burt SA. Rethinking environmental contributions to child and adolescent psychopathology: a meta-analysis of shared environmental influences. Psychol Bull. 2009;135(4):608–37. Epub 2009/07/10.

    Article  PubMed  Google Scholar 

  8. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57(11):1313–23.

    Article  PubMed  CAS  Google Scholar 

  9. Wood AC, Buitelaar J, Rijsdijk F, Asherson P, Kuntsi J. Rethinking shared environment as a source of variance underlying attention-deficit/hyperactivity disorder symptoms: comment on Burt (2009). Psychol Bull. 2010;136(3):331–40. Epub 2010/05/05.

    Article  PubMed  Google Scholar 

  10. • Anckarsater H, Lundstrom S, Kollberg L, Kerekes N, Palm C, Carlstrom E, et al. The Child and Adolescent Twin Study in Sweden (CATSS). Twin research and human genetics: the official journal of the International Society for Twin Studies. 2011;14(6):495–508. Epub 2012/04/18. This is an important, recent twin study.

    Google Scholar 

  11. • Larsson H, Anckarsater H, Rastam M, Chang Z, Lichtenstein P. Childhood attention-deficit hyperactivity disorder as an extreme of a continuous trait: a quantitative genetic study of 8,500 twin pairs. J Child Psychol Psychiatry. 2012;53(1):73–80. Epub 2011/09/20. This is an important, recent twin study.

    Article  PubMed  Google Scholar 

  12. • Nikolas MA, Burt SA. Genetic and environmental influences on ADHD symptom dimensions of inattention and hyperactivity: a meta-analysis. J Abnorm Psychol. 2010;119(1):1–17. Epub 2010/02/10. This study demonstrates the importance of investigating different dimensions of ADHD.

    Article  PubMed  Google Scholar 

  13. Boomsma DI, Saviouk V, Hottenga JJ, Distel MA, de Moor MH, Vink JM, et al. Genetic epidemiology of attention deficit hyperactivity disorder (ADHD index) in adults. PLoS One. 2010;5(5):e10621. Epub 2010/05/21.

    Article  PubMed  CAS  Google Scholar 

  14. Young SE, Friedman NP, Miyake A, Willcutt EG, Corley RP, Haberstick BC, et al. Behavioral disinhibition: liability for externalizing spectrum disorders and its genetic and environmental relation to response inhibition across adolescence. J Abnorm Psychol. 2009;118(1):117–30. Epub 2009/02/19.

    Article  PubMed  Google Scholar 

  15. Derks EM, Hudziak JJ, Dolan CV, van Beijsterveldt TC, Verhulst FC, Boomsma DI. Genetic and environmental influences on the relation between attention problems and attention deficit hyperactivity disorder. Behav Genet. 2008;38(1):11–23. Epub 2007/12/13.

    Article  PubMed  Google Scholar 

  16. Ouellet-Morin I, Wigg KG, Feng Y, Dionne G, Robaey P, Brendgen M, et al. Association of the dopamine transporter gene and ADHD symptoms in a Canadian population-based sample of same-age twins. American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics. 2008;147B(8):1442–9. Epub 2008/01/01.

    Article  CAS  Google Scholar 

  17. Haberstick BC, Timberlake D, Hopfer CJ, Lessem JM, Ehringer MA, Hewitt JK. Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder. Psychol Med. 2008;38(7):1057–66. Epub 2007/09/26.

    Article  PubMed  CAS  Google Scholar 

  18. Schultz MR, Rabi K, Faraone SV, Kremen W, Lyons MJ. Efficacy of retrospective recall of attention-deficit hyperactivity disorder symptoms: a twin study. Twin research and human genetics: the official journal of the International Society for Twin Studies. 2006;9(2):220–32. Epub 2006/04/14.

    Google Scholar 

  19. Ehringer MA, Rhee SH, Young S, Corley R, Hewitt JK. Genetic and environmental contributions to common psychopathologies of childhood and adolescence: a study of twins and their siblings. J Abnorm Child Psychol. 2006;34(1):1–17. Epub 2006/02/09.

    Article  PubMed  Google Scholar 

  20. Knopik VS, Sparrow EP, Madden PA, Bucholz KK, Hudziak JJ, Reich W, et al. Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study. Psychol Med. 2005;35(5):625–35. Epub 2005/05/28.

    Article  PubMed  Google Scholar 

  21. Kuntsi J, Rijsdijk F, Ronald A, Asherson P, Plomin R. Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood. Biol Psychiatry. 2005;57(6):647–54. Epub 2005/03/23.

    Article  PubMed  Google Scholar 

  22. Dick DM, Viken RJ, Kaprio J, Pulkkinen L, Rose RJ. Understanding the covariation among childhood externalizing symptoms: genetic and environmental influences on conduct disorder, attention deficit hyperactivity disorder, and oppositional defiant disorder symptoms. J Abnorm Child Psychol. 2005;33(2):219–29. Epub 2005/04/21.

    Article  PubMed  Google Scholar 

  23. 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(2):121–32. Epub 2005/02/03.

    Article  PubMed  Google Scholar 

  24. Saudino KJ, Ronald A, Plomin R. The etiology of behavior problems in 7-year-old twins: substantial genetic influence and negligible shared environmental influence for parent ratings and ratings by same and different teachers. J Abnorm Child Psychol. 2005;33(1):113–30. Epub 2005/03/12.

    Article  PubMed  Google Scholar 

  25. 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 Psychiatry. 2004;43(10):1267–75. Epub 2004/09/24.

    Article  PubMed  Google Scholar 

  26. 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 to 12. J Child Psychol Psychiatry. 2004;45(3):577–88. Epub 2004/04/02.

    Article  PubMed  CAS  Google Scholar 

  27. • Greven CU, Asherson P, Rijsdijk FV, Plomin R. A longitudinal twin study on the association between inattentive and hyperactive-impulsive ADHD symptoms. J Abnorm Child Psychol. 2011;39(5):623–32. Epub 2011/04/16. Longitudinal studies are extremely important since they provide insight in continuity of symptoms.

    Article  PubMed  Google Scholar 

  28. van der Valk JC, Verhulst FC, Neale MC, Boomsma DI. Longitudinal genetic analysis of problem behaviors in biologically related and unrelated adoptees. Behav Genet. 1998;28(5):365–80. Epub 1999/02/02.

    Article  PubMed  Google Scholar 

  29. Hay DA, Bennett KS, Levy F, Sergeant J, Swanson J. A twin study of attention-deficit/hyperactivity disorder dimensions rated by the strengths and weaknesses of ADHD-symptoms and normal-behavior (SWAN) scale. Biol Psychiatry. 2007;61(5):700–5. Epub 2006/09/12.

    Article  PubMed  Google Scholar 

  30. • Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet. 2009;126(1):51–90. Epub 2009/06/10. This is a thorough, well-done meta-analytic review.

    Article  PubMed  CAS  Google Scholar 

  31. Eisenberg DT, Campbell B, Gray PB, Sorenson MD. Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: an exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya. BMC Evol Biol. 2008;8:173. Epub 2008/06/12.

    Article  PubMed  CAS  Google Scholar 

  32. • Altink ME, Rommelse NN, Slaats-Willemse DI, Vasquez AA, Franke B, Buschgens CJ, et al. The dopamine receptor D4 7-repeat allele influences neurocognitive functioning, but this effect is moderated by age and ADHD status: an exploratory study. The world journal of biological psychiatry: the official journal of the World Federation of Societies of Biological Psychiatry. 2012;13(4):293–305. Epub 2011/11/25. Considering age is important given different phenotypes may manifest at different developmental stages.

    Google Scholar 

  33. Krain AL, Castellanos FX. Brain development and ADHD. Clin Psychol Rev. 2006;26(4):433–44. Epub 2006/02/17.

    Article  PubMed  Google Scholar 

  34. Polderman TJ, Posthuma D, De Sonneville LM, Stins JF, Verhulst FC, Boomsma DI. Genetic analyses of the stability of executive functioning during childhood. Biol Psychol. 2007;76(1–2):11–20. Epub 2007/06/29.

    Article  PubMed  Google Scholar 

  35. Meador-Woodruff JH, Damask SP, Wang J, Haroutunian V, Davis KL, Watson SJ. Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 1996;15(1):17–29. Epub 1996/07/01.

    Article  CAS  Google Scholar 

  36. Thompson JL, Pogue-Geile MF, Grace AA. Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms. Schizophr Bull. 2004;30(4):875–900. Epub 2005/06/15.

    Article  PubMed  Google Scholar 

  37. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH. Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem. 1995;65(3):1157–65. Epub 1995/09/01.

    Article  PubMed  CAS  Google Scholar 

  38. Franke B, Neale BM, Faraone SV. Genome-wide association studies in ADHD. Hum Genet. 2009;126(1):13–50. Epub 2009/04/23.

    Article  PubMed  CAS  Google Scholar 

  39. • Neale BM, Medland SE, Ripke S, Asherson P, Franke B, Lesch KP, et al. Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2010;49(9):884–97. Epub 2010/08/25. This is a meta-analysis of GWAS data.

    Article  PubMed  Google Scholar 

  40. Hinney A, Scherag A, Jarick I, Albayrak O, Putter C, Pechlivanis S, et al. Genome-wide association study in German patients with attention deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(8):888–97. Epub 2011/10/21.

    PubMed  Google Scholar 

  41. Stergiakouli E, Hamshere M, Holmans P, Langley K, Zaharieva I, Hawi Z, et al. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am J Psychiatry. 2012;169(2):186–94. Epub 2012/03/16.

    Article  PubMed  Google Scholar 

  42. Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet. 2006;38(9):1038–42.

    Article  PubMed  CAS  Google Scholar 

  43. Eichler EE. Widening the spectrum of human genetic variation. Nat Genet. 2006;38(1):9–11.

    Article  PubMed  CAS  Google Scholar 

  44. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004;36(9):949–51.

    Article  PubMed  CAS  Google Scholar 

  45. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, et al. Large-scale copy number polymorphism in the human genome. Science. 2004;305(5683):525–8.

    Article  PubMed  CAS  Google Scholar 

  46. Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, et al. Diet and the evolution of human amylase gene copy number variation. Nat Genet. 2007;39(10):1256–60. Epub 2007/09/11.

    Article  PubMed  CAS  Google Scholar 

  47. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55. Epub 2010/01/12.

    Article  PubMed  CAS  Google Scholar 

  48. Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet. 2010;376(9750):1401–8. Epub 2010/10/05.

    Article  PubMed  CAS  Google Scholar 

  49. Lesch KP, Selch S, Renner TJ, Jacob C, Nguyen TT, Hahn T, et al. Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree. Mol Psychiatry. 2011;16(5):491–503. Epub 2010/03/24.

    Article  PubMed  CAS  Google Scholar 

  50. Lionel AC, Crosbie J, Barbosa N, Goodale T, Thiruvahindrapuram B, Rickaby J, et al. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med. 2011;3(95):95ra75. Epub 2011/08/13.

    Article  PubMed  CAS  Google Scholar 

  51. • Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet. 2012;44(1):78–84. Epub 2011/12/06. This paper offers important CNV data supporting rare variants affecting glutamatergic pathways explaining up to 10 % of ADHD cases.

    Article  CAS  Google Scholar 

  52. • Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry. 2012;169(2):195–204. Epub 2012/03/16. This paper presents important CNV data supporting rare variants that play a significant role in ADHD.

    Article  PubMed  Google Scholar 

  53. Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry. 2010;15(6):637–46. Epub 2009/06/24.

    Article  PubMed  CAS  Google Scholar 

  54. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4(2):143–53. Epub 2004/01/21.

    Article  PubMed  CAS  Google Scholar 

  55. Kelleher 3rd RJ, Bear MF. The autistic neuron: troubled translation? Cell. 2008;135(3):401–6. Epub 2008/11/06.

    Article  PubMed  CAS  Google Scholar 

  56. Auerbach BD, Osterweil EK, Bear MF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature. 2011;480(7375):63–8. Epub 2011/11/25.

    Article  PubMed  CAS  Google Scholar 

  57. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–8.

    Article  PubMed  CAS  Google Scholar 

  58. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3(9):662–73. Epub 2002/09/05.

    Article  PubMed  CAS  Google Scholar 

  59. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8(5):355–67. Epub 2007/04/25.

    Article  PubMed  CAS  Google Scholar 

  60. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA. 2008;299(11):1345–50. Epub 2008/03/20.

    Article  PubMed  CAS  Google Scholar 

  61. Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–12. Epub 2007/05/25.

    Article  PubMed  CAS  Google Scholar 

  62. Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 2010;329(5990):444–8. Epub 2010/07/24.

    Article  PubMed  CAS  Google Scholar 

  63. Holliday R. Epigenetics: a historical overview. Epigenetics: official journal of the DNA Methylation Society. 2006;1(2):76–80. Epub 2007/11/14.

    Google Scholar 

  64. Henikoff S, Matzke MA. Exploring and explaining epigenetic effects. Trends in genetics: TIG. 1997;13(8):293–5. Epub 1997/08/01.

    Article  PubMed  CAS  Google Scholar 

  65. Elia J, Laracy S, Allen J, Nissley-Tsiopinis J, Borgmann-Winter K. Epigenetics: genetics versus life experiences. Curr Top Behav Neurosci. 2012;9:317–40. Epub 2011/07/06.

    Article  PubMed  Google Scholar 

  66. • Archer T, Oscar-Berman M, Blum K. Epigenetics in developmental disorder: ADHD and endophenotypes. Journal of Genetic Syndrome & Gene Therapy. 2011;2(104). Epub 2012/01/09. This paper looks at important epigenetic factors relevant to ADHD.

  67. • Vucetic Z, Totoki K, Schoch H, Whitaker KW, Hill-Smith T, Lucki I, et al. Early life protein restriction alters dopamine circuitry. Neuroscience. 2010;168(2):359–70. Epub 2010/04/17. This important paper focuses on prenatal diet and its effect on dopaminergic system.

    Article  PubMed  CAS  Google Scholar 

  68. Vucetic Z, Kimmel J, Totoki K, Hollenbeck E, Reyes TM. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology. 2010;151(10):4756–64. Epub 2010/08/06.

    Article  PubMed  CAS  Google Scholar 

  69. Andrews SC, Wood MD, Tunster SJ, Barton SC, Surani MA, John RM. Cdkn1c (p57Kip2) is the major regulator of embryonic growth within its imprinted domain on mouse distal chromosome 7. BMC Dev Biol. 2007;7:53. Epub 2007/05/23.

    Article  PubMed  CAS  Google Scholar 

  70. Hultman CM, Torrang A, Tuvblad C, Cnattingius S, Larsson JO, Lichtenstein P. Birth weight and attention-deficit/hyperactivity symptoms in childhood and early adolescence: a prospective Swedish twin study. J Am Acad Child Adolesc Psychiatry. 2007;46(3):370–7.

    Article  PubMed  Google Scholar 

  71. Eubig PA, Aguiar A, Schantz SL. Lead and PCBs as risk factors for attention deficit/hyperactivity disorder. Environ Health Perspect. 2010;118(12):1654–67. Epub 2010/09/11.

    Article  PubMed  CAS  Google Scholar 

  72. Cho SC, Kim BN, Hong YC, Shin MS, Yoo HJ, Kim JW, et al. Effect of environmental exposure to lead and tobacco smoke on inattentive and hyperactive symptoms and neurocognitive performance in children. J Child Psychol Psychiatry. 2010;51(9):1050–7. Epub 2010/04/22.

    Article  PubMed  Google Scholar 

  73. Kapoor A, Petropoulos S, Matthews SG. Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids. Brain Res Rev. 2008;57(2):586–95. Epub 2007/08/25.

    Article  PubMed  CAS  Google Scholar 

  74. Linnet KM, Wisborg K, Obel C, Secher NJ, Thomsen PH, Agerbo E, et al. Smoking during pregnancy and the risk for hyperkinetic disorder in offspring. Pediatrics. 2005;116(2):462–7.

    Article  PubMed  Google Scholar 

  75. 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 Psychiatry. 2003;160(11):1985–9. Epub 2003/11/05.

    Article  PubMed  Google Scholar 

  76. Kotimaa AJ, Moilanen I, Taanila A, Ebeling H, Smalley SL, McGough JJ, et al. Maternal smoking and hyperactivity in 8-year-old children. J Am Acad Child Adolesc Psychiatry. 2003;42(7):826–33.

    Article  PubMed  Google Scholar 

  77. Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. Case-control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. J Am Acad Child Adolesc Psychiatry. 2002;41(4):378–85. Epub 2002/04/05.

    Article  PubMed  Google Scholar 

  78. Milberger S, Biederman J, Faraone SV, Chen L, Jones J. Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry. 1996;153(9):1138–42. Epub 1996/09/01.

    PubMed  CAS  Google Scholar 

  79. Milberger S, Biederman J, Faraone SV, Chen L, Jones J. Further evidence of an association between attention-deficit/hyperactivity disorder and cigarette smoking. Findings from a high-risk sample of siblings. Am J Addict. 1997;6(3):205–17. Epub 1997/07/01.

    PubMed  CAS  Google Scholar 

  80. McIntosh DE, Mulkins RS, Dean RS. Utilization of maternal perinatal risk indicators in the differential diagnosis of ADHD and UADD children. Int J Neurosci. 1995;81(1-2):35–46. Epub 1995/03/01.

    Article  PubMed  CAS  Google Scholar 

  81. Neuman RJ, Lobos E, Reich W, Henderson CA, Sun LW, Todd RD. Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype. Biol Psychiatry. 2006.

  82. Langley K, Rice F, van den Bree MB, Thapar A. Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. A review. Minerva Pediatr. 2005;57(6):359–71.

    PubMed  CAS  Google Scholar 

  83. Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect. 2006;114(12):1904–9. Epub 2006/12/23.

    PubMed  Google Scholar 

  84. O’Connor TG, Heron J, Golding J, Beveridge M, Glover V. Maternal antenatal anxiety and children’s behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Br J Psychiatry. 2002;180:502–8. Epub 2002/06/04.

    Article  PubMed  Google Scholar 

  85. Fried PA, Makin JE. Neonatal behavioural correlates of prenatal exposure to marihuana, cigarettes and alcohol in a low risk population. Neurotoxicol Teratol. 1987;9(1):1–7. Epub 1987/01/01.

    Article  PubMed  CAS  Google Scholar 

  86. Naeye RL, Peters EC. Mental development of children whose mothers smoked during pregnancy. Obstet Gynecol. 1984;64(5):601–7. Epub 1984/11/01.

    PubMed  CAS  Google Scholar 

  87. O’Callaghan MJ, Williams GM, Andersen MJ, Bor W, Najman JM. Obstetric and perinatal factors as predictors of child behaviour at 5 years. J Paediatr Child Health. 1997;33(6):497–503. Epub 1998/03/04.

    Article  PubMed  Google Scholar 

  88. Huizink AC, Mulder EJ. Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev. 2006;30(1):24–41.

    Article  PubMed  CAS  Google Scholar 

  89. Knopik VS, Heath AC, Jacob T, Slutske WS, Bucholz KK, Madden PA, et al. Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design. Psychol Med. 2006;36(10):1461–71.

    Article  PubMed  Google Scholar 

  90. Nigg JT, Breslau N. Prenatal smoking exposure, low birth weight, and disruptive behavior disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(3):362–9.

    Article  PubMed  Google Scholar 

  91. Haavik J, Halmoy A, Hegvik T-A, Johansson S. Maternal genotypes as predictors of offspring mental health: the next frontier of genomic medicine? Futur Neurol. 2011;6:731–43.

    Article  CAS  Google Scholar 

  92. Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A, et al. A longitudinal study of epigenetic variation in twins. Epigenetics: official journal of the DNA Methylation Society. 2010;5(6):516–26. Epub 2010/05/28.

    CAS  Google Scholar 

  93. • Shumay E, Fowler JS, Volkow ND. Genomic features of the human dopamine transporter gene and its potential epigenetic States: implications for phenotypic diversity. PLoS One. 2010;5(6):e11067. Epub 2010/06/16. This paper focuses on characteristics of genes and what makes them vulnerable to epigenetic effects.

    Article  PubMed  CAS  Google Scholar 

  94. Choudhry Z, Sengupta SM, Grizenko N, Fortier ME, Thakur GA, Bellingham J, et al. LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy. Journal of child psychology and psychiatry, and allied disciplines. 2012. Epub 2012/04/11.

  95. Baird AL, Coogan AN, Siddiqui A, Donev RM, Thome J. Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels. Mol Psychiatry. 2011. Epub 2011/11/23.

  96. Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, et al. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J Clin Invest. 2011;121(9):3479–91. Epub 2011/08/02.

    Article  PubMed  CAS  Google Scholar 

  97. Shishkina GT, Kalinina TS, Dygalo NN. Attenuation of alpha2A-adrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood. Neuroscience. 2004;129(3):521–8. Epub 2004/11/16.

    Article  PubMed  CAS  Google Scholar 

  98. Swanson JM, Volkow ND. Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD. Behav Brain Res. 2002;130(1–2):73–8. Epub 2002/02/28.

    Article  PubMed  CAS  Google Scholar 

  99. Adriani W, Leo D, Guarino M, Natoli A, Di Consiglio E, De Angelis G, et al. Short-term effects of adolescent methylphenidate exposure on brain striatal gene expression and sexual/endocrine parameters in male rats. Ann N Y Acad Sci. 2006;1074:52–73. Epub 2006/11/16.

    Article  PubMed  CAS  Google Scholar 

  100. Yano M, Steiner H. Topography of methylphenidate (ritalin)-induced gene regulation in the striatum: differential effects on c-fos, substance P and opioid peptides. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 2005;30(5):901–15. Epub 2005/01/08.

    Article  CAS  Google Scholar 

  101. Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci U S A. 1996;93(24):14128–33. Epub 1996/11/26.

    Article  PubMed  CAS  Google Scholar 

  102. Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics. 2010;11(3):407–19. Epub 2010/03/20.

    Article  PubMed  CAS  Google Scholar 

  103. Froehlich T, McGough J, Stein MA. Progress and promise of ADHD pharmacogenetics. CNS Drugs. 2010;24(2):99–117.

    Article  PubMed  CAS  Google Scholar 

  104. Polanczyk G, Bigarella MP, Hutz MH, Rohde LA. Pharmacogenetic approach for a better drug treatment in children. Curr Pharm Des. 2010;16(22):2462–73. Epub 2010/06/02.

    Article  PubMed  CAS  Google Scholar 

  105. Froehlich TE, Epstein JN, Nick TG, Melguizo Castro MS, Stein MA, Brinkman WB, et al. Pharmacogenetic predictors of methylphenidate dose-response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(11):1129–39. Epub 2011/10/26.

    Article  PubMed  Google Scholar 

  106. Mick E, Neale B, Middleton FA, McGough JJ, Faraone SV. Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(8):1412–8.

    Article  PubMed  CAS  Google Scholar 

  107. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003;100(10):6186–91.

    Article  PubMed  CAS  Google Scholar 

  108. Hamidovic A, Dlugos A, Palmer AA, de Wit H. Polymorphisms in dopamine transporter (SLC6A3) are associated with stimulant effects of D-amphetamine: an exploratory pharmacogenetic study using healthy volunteers. Behav Genet. 2010;40(2):255–61. Epub 2010/01/22.

    Article  PubMed  Google Scholar 

  109. Gruber R, Joober R, Grizenko N, Leventhal BL, Cook Jr EH, Stein MA. Dopamine transporter genotype and stimulant side effect factors in youth diagnosed with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19(3):233–9. Epub 2009/06/13.

    Article  PubMed  Google Scholar 

  110. Mick E, McGough JJ, Middleton FA, Neale B, Faraone SV. Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):466–72. Epub 2010/12/07.

    Article  PubMed  CAS  Google Scholar 

  111. Cho SC, Kim BN, Cummins TD, Kim JW, Bellgrove MA. Norepinephrine transporter -3081(A/T) and alpha-2A-adrenergic receptor MspI polymorphisms are associated with cardiovascular side effects of OROS-methylphenidate treatment. J Psychopharmacol. 2012;26(3):380–9. Epub 2011/06/02.

    Article  PubMed  CAS  Google Scholar 

  112. Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL, et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2007;81(3):346–53. Epub 2007/03/07.

    Article  PubMed  CAS  Google Scholar 

  113. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241–8.

    Article  PubMed  CAS  Google Scholar 

  114. Nemoda Z, Angyal N, Tarnok Z, Gadoros J, Sasvari-Szekely M. Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD. Neuropharmacology. 2009;57(7–8):731–3. Epub 2009/09/08.

    Article  PubMed  CAS  Google Scholar 

  115. Michelson D, Read HA, Ruff DD, Witcher J, Zhang S, McCracken J. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2007;46(2):242–51. Epub 2007/01/24.

    Article  PubMed  Google Scholar 

  116. Trzepacz PT, Williams DW, Feldman PD, Wrishko RE, Witcher JW, Buitelaar JK. CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol. 2008;18(2):79–86. Epub 2007/08/19.

    Article  PubMed  CAS  Google Scholar 

  117. ter Laak MA, Temmink AH, Koeken A, van ‘t Veer NE, van Hattum PR, Cobbaert CM. Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity. Pediatr Neurol. 2010;43(3):159–62. Epub 2010/08/10.

    Article  PubMed  Google Scholar 

  118. Scherer D, Hassel D, Bloehs R, Zitron E, von Lowenstern K, Seyler C, et al. Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents. Br J Pharmacol. 2009;156(2):226–36. Epub 2009/01/22.

    Article  PubMed  CAS  Google Scholar 

  119. Sawant S, Daviss SR. Seizures and prolonged QTc with atomoxetine overdose. Am J Psychiatry. 2004;161(4):757. Epub 2004/04/02.

    Article  PubMed  Google Scholar 

  120. Barker MJ, Benitez JG, Ternullo S, Juhl GA. Acute oxcarbazepine and atomoxetine overdose with quetiapine. Vet Hum Toxicol. 2004;46(3):130–2. Epub 2004/06/03.

    PubMed  Google Scholar 

  121. Kiehn J, Lacerda AE, Brown AM. Pathways of HERG inactivation. Am J Physiol. 1999;277(1 Pt 2):H199–210. Epub 1999/07/17.

    PubMed  CAS  Google Scholar 

  122. O’Rourke JA, Scharf JM, Yu D, Pauls DL. The genetics of Tourette syndrome: a review. J Psychosom Res. 2009;67(6):533–45. Epub 2009/11/17.

    Article  PubMed  Google Scholar 

  123. Mathews CA, Grados MA. Familiality of Tourette syndrome, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder: heritability analysis in a large sib-pair sample. J Am Acad Child Adolesc Psychiatry. 2011;50(1):46–54. Epub 2010/12/16.

    Article  PubMed  Google Scholar 

  124. Geller D, Petty C, Vivas F, Johnson J, Pauls D, Biederman J. Further evidence for co-segregation between pediatric obsessive compulsive disorder and attention deficit hyperactivity disorder: a familial risk analysis. Biol Psychiatry. 2007;61(12):1388–94. Epub 2007/01/24.

    Article  PubMed  Google Scholar 

  125. DeMille MM, Kidd JR, Ruggeri V, Palmatier MA, Goldman D, Odunsi A, et al. Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum Genet. 2002;111(6):521–37.

    Article  PubMed  CAS  Google Scholar 

  126. Mrazek DA. Current applications of clinical genetic testing for psychiatric practice. Minn Med. 2007;90(1):42–43

    PubMed  Google Scholar 

  127. Lyon GJ, Jiang T, Van Wijk R, Wang W, Bodily PM, Xing J, et al. Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications. Discov Med. 2011;12(62):41–55. Epub 2011/07/29.

    PubMed  Google Scholar 

  128. Homer N, Szelinger S, Redman M, Duggan D, Tembe W, Muehling J, et al. Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays. PLoS Genet. 2008;4(8):e1000167. Epub 2008/09/05.

    Article  PubMed  CAS  Google Scholar 

  129. Braun R, Rowe W, Schaefer C, Zhang J, Buetow K. Needles in the haystack: identifying individuals present in pooled genomic data. PLoS Genet. 2009;5(10):e1000668. Epub 2009/10/03.

    Article  PubMed  CAS  Google Scholar 

  130. Clifton JM, VanBeuge SS, Mladenka C, Wosnik KK. The genetic information nondiscrimination act 2008: what clinicians should understand. J Am Acad Nurse Pract. 2010;22(5):246–9. Epub 2010/05/27.

    Article  PubMed  Google Scholar 

  131. Vaccarino FM, Urban AE, Stevens HE, Szekely A, Abyzov A, Grigorenko EL, et al. Annual research review: the promise of stem cell research for neuropsychiatric disorders. J Child Psychol Psychiatry. 2011;52(4):504–16. Epub 2011/01/06.

    Article  PubMed  Google Scholar 

  132. Hess EJ, Collins KA, Wilson MC. Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation. The Journal of neuroscience: the official journal of the Society for Neuroscience. 1996;16(9):3104–11. Epub 1996/05/01.

    CAS  Google Scholar 

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Disclosure

J. Elia: none; J. Sackett: none; T. Turner: none; M. Schardt: none; S. -C. Tang: none; N. Kurtz: none; M. Dunfey: none; N. A. McFarlane: none; A. Susi: none; D. Danish: none; A. Li: none; J. Nissley-Tsiopinis: research funding from Shire Pharmaceutical; K. Borgmann-Winter: research funding from National Institutes of Health and Pfizer.

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  1. Department Psychiatry, The University of Pennsylvania, Philadelphia, PA, 19104-6209, USA

    Josephine Elia

  2. Department of Child and Adolescent Psychiatry, The Children’s Hospital of Philadelphia, Science Center, 3440 Market St., Suite 200, Philadelphia, PA, 19104, USA

    Jillan Sackett, Terri Turner, Nicole Kurtz, Maura Dunfey, Nadia A. McFarlane, Aita Susi, David Danish, Alice Li, Jenelle Nissley-Tsiopinis & Karin Borgmann-Winter

  3. Trinity College, 300 Summit St., Hartford, CT, 06106, USA

    Martin Schardt

  4. Department of Child and Adolescent Psychiatry, The Children’s Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, 19104-6209, USA

    Shih-Ching Tang

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Elia, J., Sackett, J., Turner, T. et al. Attention-Deficit/Hyperactivity Disorder Genomics: Update for Clinicians. Curr Psychiatry Rep 14, 579–589 (2012). https://doi.org/10.1007/s11920-012-0309-4

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