Should we keep on? Looking into pharmacogenomics of ADHD in adulthood from a different perspective

Papers of special note have been highlighted as: • of interest

References

• 1 Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol. Med. 36(2), 159–165 (2006).
  MedlineGoogle Scholar
• 2 Kessler RC, Adler L, Barkley R et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am. J. Psychiatry 163(4), 716–723 (2006).
  MedlineGoogle Scholar
• 3 Franke B, Faraone SV, Asherson P et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol. Psychiatry 17(10), 960–987 (2012).• A comprehensive review of genetics of attention-deficit/hyperactivity disorder (ADHD) in adults.
  Medline CASGoogle Scholar
• 4 Chang Z, Lichtenstein P, Asherson PJ, Larsson H. Developmental twin study of attention problems: high heritabilities throughout development. JAMA Psychiatry 70(3), 311–318 (2013).
  MedlineGoogle Scholar
• 5 Faraone SV, Perlis RH, Doyle AE et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol. Psychiatry 57(11), 1313–1323 (2005).
  Medline CASGoogle Scholar
• 6 Surman CB, Hammerness PG, Pion K, Faraone SV. Do stimulants improve functioning in adults with ADHD? A review of the literature. Eur. Neuropsychopharmacol. 23(6), 528–533 (2013).
  Medline CASGoogle Scholar
• 7 Fredriksen M, Halmoy A, Faraone SV, Haavik J. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies. Eur. Neuropsychopharmacol. 23(6), 508–527 (2013).
  Medline CASGoogle Scholar
• 8 Koesters M, Becker T, Kilian R, Fegert JM, Weinmann S. Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder. J. Psychopharmacol. 23(7), 733–744 (2009).
  Medline CASGoogle Scholar
• 9 Castells X, Ramos-Quiroga JA, Rigau D et al. Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS Drugs 25(2), 157–169 (2011).
  Medline CASGoogle Scholar
• 10 Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J. Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder. J. Clin. Psychopharmacol. 24(1), 24–29 (2004).
  Medline CASGoogle Scholar
• 11 Victor MM, Grevet EH, Salgado CA et al. Reasons for pretreatment attrition and dropout from methylphenidate in adults with attention-deficit/hyperactivity disorder: the role of comorbidities. J. Clin. Psychopharmacol. 29(6), 614–616 (2009).
  MedlineGoogle Scholar
• 12 Buitelaar JK, Kooij JJ, Ramos-Quiroga JA et al. Predictors of treatment outcome in adults with ADHD treated with OROS^® methylphenidate. Prog. Neuropsychopharmacol. Biol. Psychiatry 35(2), 554–560 (2011).
  Medline CASGoogle Scholar
• 13 Victor MM, Rovaris DL, Salgado CA et al. Severity but not comorbidities predicts response to methylphenidate in adults with ADHD: results from a natu-ralistic study. J. Clin. Psychopharmacol. 34(2), 212–217 (2014).
  MedlineGoogle Scholar
• 14 Contini V, Rovaris DL, Victor MM, Grevet EH, Rohde LA, Bau CH. Pharmacogenetics of response to methylphenidate in adult patients with attention-deficit/hyperactivity disorder (ADHD): a systematic review. Eur. Neuropsychopharmacol. 23(6), 555–560 (2013).
  Medline CASGoogle Scholar
• 15 Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol. Psychiatry 17(8), 760–769 (2012).
  Medline CASGoogle Scholar
• 16 Contini V, Victor MM, Bertuzzi GP et al. No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD. J. Clin. Psychopharmacol. 32(6), 820–823 (2012).• Before the submission of the present review, this was the last study published aiming to evaluate methylphenidate response in adults with ADHD.
  Medline CASGoogle Scholar
• 17 Contini V, Victor MM, Cerqueira CC et al. Adrenergic alpha2A receptor gene is not associated with methylphenidate response in adults with ADHD. Eur. Arch. Psychiatry Clin. Neurosci. 261(3), 205–211 (2011).• First study evaluating the role of the adrenergic α2A receptor gene on methylphenidate response in adults with ADHD.
  MedlineGoogle Scholar
• 18 Contini V, Victor MM, Marques FZ et al. Response to methylphenidate is not influenced by DAT1 polymorphisms in a sample of Brazilian adult patients with ADHD. J. Neural. Transm. 117(2), 269–276 (2010).• First study evaluating methylphenidate response in adults conducted outside the USA and Europe.
  Medline CASGoogle Scholar
• 19 Kooij JS, Boonstra AM, Vermeulen SH et al. Response to methylphenidate in adults with ADHD is associated with a polymorphism in SLC6A3 (DAT1). Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(2), 201–208 (2008).• Second study evaluating methylphenidate response conducted in adults with ADHD.
  MedlineGoogle Scholar
• 20 Mick E, Biederman J, Spencer T, Faraone SV, Sklar P. Absence of association with DAT1 polymorphism and response to methylphenidate in a sample of adults with ADHD. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B(8), 890–894 (2006).• First study evaluating methylphenidate response conducted in adults with ADHD.
  Medline CASGoogle Scholar
• 21 Sadee W. The relevance of “missing heritability” in pharmacogenomics. Clin. Pharmacol. Ther. 92(4), 428–430 (2012).
  Medline CASGoogle Scholar
• 22 Arnsten AF, Pliszka SR. Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacol. Biochem. Behav. 99(2), 211–216 (2011).
  Medline CASGoogle Scholar
• 23 Wilens TE. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder. J. Clin. Psychopharmacol. 28(3 Suppl. 2), S46–S53 (2008).
  Medline CASGoogle Scholar
• 24 Davies SM. Pharmacogenetics, pharmacogenomics and personalized medicine: are we there yet? Hematology Am. Soc. Hematol. Educ. Program 111–117 (2006).
  MedlineGoogle Scholar
• 25 Weinshilboum R. Inheritance and drug response. N. Engl. J. Med. 348(6), 529–537 (2003).
  MedlineGoogle Scholar
• 26 Nguyen CM, Mendes MA, Ma JD. Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. PLoS Curr. 3, RRN1236 (2011).
  MedlineGoogle Scholar
• 27 Kimko HC, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin. Pharmacokinet. 37(6), 457–470 (1999).
  Medline CASGoogle Scholar
• 28 Gualtieri CT, Wargin W, Kanoy R et al. Clinical studies of methylphenidate serum levels in children and adults. J. Am. Acad. Child Psychiatry 21(1), 19–26 (1982).
  Medline CASGoogle Scholar
• 29 Shaywitz SE, Hunt RD, Jatlow P et al. Psychopharmacology of attention deficit disorder: pharmacokinetic, neuroendocrine, and behavioral measures following acute and chronic treatment with methylphenidate. Pediatrics 69(6), 688–694 (1982).
  Medline CASGoogle Scholar
• 30 Faraj BA, Israili ZH, Perel JM et al. Metabolism and disposition of methylphenidate-14C: studies in man and animals. J. Pharmacol. Exp. Ther. 191(3), 535–547 (1974).
  Medline CASGoogle Scholar
• 31 Patrick KS, Caldwell RW, Ferris RM, Breese GR. Pharmacology of the enantiomers of threo-methylphenidate. J. Pharmacol. Exp. Ther. 241(1), 152–158 (1987).
  Medline CASGoogle Scholar
• 32 Srinivas NR, Hubbard JW, Quinn D, Midha KK. Enantioselective pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder. Clin. Pharmacol. Ther. 52(5), 561–568 (1992).
  Medline CASGoogle Scholar
• 33 Markowitz JS, Patrick KS. Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? J. Clin. Psychopharmacol. 28(3 Suppl. 2), S54–S61 (2008).
  Medline CASGoogle Scholar
• 34 Lim HK, Hubbard JW, Midha KK. Development of enantioselective gas chromatographic quantitation assay for dl-threo-methylphenidate in biological fluids. J. Chromatogr. 378(1), 109–123 (1986).
  Medline CASGoogle Scholar
• 35 Modi NB, Wang B, Noveck RJ, Gupta SK. Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system. J. Clin. Pharmacol. 40(10), 1141–1149 (2000).
  Medline CASGoogle Scholar
• 36 Srinivas NR, Hubbard JW, Korchinski ED, Midha KK. Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans. Pharm. Res. 10(1), 14–21 (1993).
  Medline CASGoogle Scholar
• 37 Srinivas NR, Quinn D, Hubbard JW, Midha KK. Stereoselective disposition of methylphenidate in children with attention-deficit disorder. J. Pharmacol. Exp. Ther. 241(1), 300–306 (1987).
  Medline CASGoogle Scholar
• 38 Markowitz JS, Morrison SD, Devane CL. Drug interactions with psychostimulants. Int. Clin. Psychopharmacol. 14(1), 1–18 (1999).
  Medline CASGoogle Scholar
• 39 Devane CL, Markowitz JS, Carson SW et al. Single-dose pharmacokinetics of methylphenidate in CYP2D6 extensive and poor metabolizers. J. Clin. Psychopharmacol. 20(3), 347–349 (2000).
  Medline CASGoogle Scholar
• 40 Sun Z, Murry DJ, Sanghani SP et al. Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J. Pharmacol. Exp. Ther. 310(2), 469–476 (2004).
  Medline CASGoogle Scholar
• 41 Zhu HJ, Patrick KS, Yuan HJ et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am. J. Hum. Genet. 82(6), 1241–1248 (2008).
  Medline CASGoogle Scholar
• 42 Bruxel EM, Salatino-Oliveira A, Genro JP et al. Association of a carboxylesterase 1 polymorphism with appetite reduction in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate. Pharmacogenomics J. 13(5), 476–480 (2013).
  Medline CASGoogle Scholar
• 43 Johnson KA, Barry E, Lambert D et al. Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J. Child. Adolesc. Psychopharmacol. 23(10), 655–664 (2013).
  Medline CASGoogle Scholar
• 44 Nemoda Z, Angyal N, Tarnok Z, Gadoros J, Sasvari-Szekely M. Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD. Neuropharmacology 57(7–8), 731–733 (2009).
  Medline CASGoogle Scholar
• 45 Franceschini A, Szklarczyk D, Frankild S et al. STRING v9.1: protein–protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 41(Database issue), D808–D815 (2013).
  Medline CASGoogle Scholar
• 46 STRING 9.1. http://string-db.org
  Google Scholar
• 47 Kuhn M, Szklarczyk D, Pletscher-Frankild S et al. STITCH 4: integration of protein-chemical interactions with user data. Nucleic Acids Res. 42(1), D401–407 (2014).
  Medline CASGoogle Scholar
• 48 STITCH 4.0. http://stitch.embl.de
  Google Scholar
• 49 Sutton RB, Fasshauer D, Jahn R, Brunger AT. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 395(6700), 347–353 (1998).
  Medline CASGoogle Scholar
• 50 Zylbersztejn K, Galli T. Vesicular traffic in cell navigation. FEBS J 278(23), 4497–4505 (2011).
  Medline CASGoogle Scholar
• 51 McGough J, Mccracken J, Swanson J et al. Pharmacogenetics of methylphenidate response in preschoolers with ADHD. J. Am. Acad. Child. Adolesc. Psychiatry 45(11), 1314–1322 (2006).
  MedlineGoogle Scholar
• 52 McGough JJ, Mccracken JT, Loo SK et al. A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder. J. Am. Acad. Child. Adolesc. Psychiatry 48(12), 1155–1164 (2009).
  MedlineGoogle Scholar
• 53 Bartl J, Link P, Schlosser C et al. Effects of methylphenidate: the cellular point of view. Atten Defic Hyperact Disord 2(4), 225–232 (2010).
  MedlineGoogle Scholar
• 54 Chang S, Zhang W, Gao L, Wang J. Prioritization of candidate genes for attention deficit hyperactivity disorder by computational analysis of multiple data sources. Protein Cell 3(7), 526–534 (2012).
  Medline CASGoogle Scholar
• 55 Guan L, Wang B, Chen Y et al. A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population. Mol. Psychiatry 14(5), 546–554 (2009).
  Medline CASGoogle Scholar
• 56 Lasky-Su J, Anney RJ, Neale BM et al. Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(8), 1355–1358 (2008).
  MedlineGoogle Scholar
• 57 Sanchez-Mora C, Cormand B, Ramos-Quiroga JA et al. Evaluation of common variants in 16 genes involved in the regulation of neurotransmitter release in ADHD. Eur. Neuropsychopharmacol. 23(6), 426–435 (2013).
  Medline CASGoogle Scholar
• 58 Guimaraes AP, Zeni C, Polanczyk G et al. MAOA is associated with methylphenidate improvement of oppositional symptoms in boys with attention deficit hyperactivity disorder. Int. J. Neuropsychopharmacol. 12(5), 709–714 (2009).
  Medline CASGoogle Scholar
• 59 Biederman J, Kim JW, Doyle AE et al. Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(8), 1511–1518 (2008).
  Medline CASGoogle Scholar
• 60 Brookes K, Xu X, Chen W et al. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol. Psychiatry 11(10), 934–953 (2006).
  Medline CASGoogle Scholar
• 61 Das M, Bhowmik AD, Sinha S et al. MAOA promoter polymorphism and attention deficit hyperactivity disorder (ADHD) in indian children. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B(6), 637–642 (2006).
  Medline CASGoogle Scholar
• 62 Das M, Das Bhowmik A, Bhaduri N et al. Role of gene–gene/gene–environment interaction in the etiology of eastern Indian ADHD probands. Prog. Neuropsychopharmacol. Biol. Psychiatry 35(2), 577–587 (2011).
  Medline CASGoogle Scholar
• 63 Domschke K, Sheehan K, Lowe N et al. Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B(1), 110–114 (2005).
  MedlineGoogle Scholar
• 64 Fowler T, Langley K, Rice F et al. Psychopathy trait scores in adolescents with childhood ADHD: the contribution of genotypes affecting MAOA, 5HTT and COMT activity. Psychiatr. Genet. 19(6), 312–319 (2009).
  MedlineGoogle Scholar
• 65 Jiang S, Xin R, Lin S et al. Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes. Am. J. Med. Genet. 105(8), 783–788 (2001).
  Medline CASGoogle Scholar
• 66 Li J, Kang C, Zhang H et al. Monoamine oxidase A gene polymorphism predicts adolescent outcome of attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B(4), 430–433 (2007).
  Medline CASGoogle Scholar
• 67 Li JJ, Lee SS. Association of positive and negative parenting behavior with childhood ADHD: interactions with offspring monoamine oxidase A (MAO-A) genotype. J. Abnorm. Child Psychol. 40(2), 165–175 (2012).
  Medline CASGoogle Scholar
• 68 Manor I, Tyano S, Mel E et al. Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA). Mol. Psychiatry 7(6), 626–632 (2002).
  Medline CASGoogle Scholar
• 69 Liu L, Guan LL, Chen Y et al. Association analyses of MAOA in Chinese Han subjects with attention-deficit/hyperactivity disorder: family-based association test, case–control study, and quantitative traits of impulsivity. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B(6), 737–748 (2011).
  MedlineGoogle Scholar
• 70 Li J, Wang Y, Hu S et al. The monoamine oxidase B gene exhibits significant association to ADHD. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147(3), 370–374 (2008).
  MedlineGoogle Scholar
• 71 NCBI Gene. www.ncbi.nlm.nih.gov/gene
  Google Scholar
• 72 Nymberg C, Jia T, Lubbe S et al. Neural mechanisms of attention-deficit/hyperactivity disorder symptoms are stratified by MAOA genotype. Biol. Psychiatry 74(8), 607–614 (2013).
  Medline CASGoogle Scholar
• 73 Roohi J, Devincent CJ, Hatchwell E, Gadow KD. Association of a monoamine oxidase-a gene promoter polymorphism with ADHD and anxiety in boys with autism spectrum disorder. J. Autism Dev. Disord. 39(1), 67–74 (2009).
  MedlineGoogle Scholar
• 74 Xu X, Brookes K, Chen CK, Huang YS, Wu YY, Asherson P. Association study between the monoamine oxidase A gene and attention deficit hyperactivity disorder in Taiwanese samples. BMC Psychiatry 7, 10 (2007).
  MedlineGoogle Scholar
• 75 Oades RD, Lasky-Su J, Christiansen H et al. The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behav. Brain Funct. 4, 48 (2008).
  MedlineGoogle Scholar
• 76 Ribases M, Ramos-Quiroga JA, Hervas A et al. Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. Mol. Psychiatry 14(1), 71–85 (2009).
  Medline CASGoogle Scholar
• 77 Eisbach SE, Outeiro TF. Alpha-synuclein and intracellular trafficking: impact on the spreading of Parkinson's disease pathology. J. Mol. Med. (Berl.) 91(6), 693–703 (2013).
  Medline CASGoogle Scholar
• 78 Surguchov A. Synucleins: are they two-edged swords? J. Neurosci. Res. 91(2), 161–166 (2013).
  Medline CASGoogle Scholar
• 79 Elia J, Gai X, Xie HM et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol. Psychiatry 15(6), 637–646 (2010).
  Medline CASGoogle Scholar
• 80 Jarick I, Volckmar AL, Putter C et al. Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Mol. Psychiatry 19(1), 115–121 (2014).
  Medline CASGoogle Scholar
• 81 Jiang H, Jiang Q, Feng J. Parkin increases dopamine uptake by enhancing the cell surface expression of dopamine transporter. J. Biol. Chem. 279(52), 54380–54386 (2004).
  Medline CASGoogle Scholar
• 82 Jiang H, Jiang Q, Liu W, Feng J. Parkin suppresses the expression of monoamine oxidases. J. Biol. Chem. 281(13), 8591–8599 (2006).
  Medline CASGoogle Scholar
• 83 Zhang H, Zhu S, Zhu Y, Chen J, Zhang G, Chang H. An association study between SNAP-25 gene and attention-deficit hyperactivity disorder. Eur. J. Paediatr. Neurol. 15(1), 48–52 (2011).
  MedlineGoogle Scholar
• 84 Gao XP, Su LY, Zhao AL, Luo XR, Xia K. [Association of 14 polymorphisms in the five candidate genes and attention deficit hyperactivity disorder]. Zhongguo Dang Dai Er Ke Za Zhi 11(8), 617–622 (2009).
  Medline CASGoogle Scholar
• 85 Elia J, Capasso M, Zaheer Z et al. Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1A. Psychiatr Genet 19(3), 134–141 (2009).
  MedlineGoogle Scholar
• 86 Lasky-Su J, Neale BM, Franke B et al. Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(8), 1345–1354 (2008).
  Medline CASGoogle Scholar
• 87 Galvez JM, Forero DA, Fonseca DJ, Mateus HE, Talero-Gutierrez C, Velez-Van-Meerbeke A. Evidence of association between SNAP25 gene and attention deficit hyperactivity disorder in a Latin American sample. Atten. Defic. Hyperact. Disord. 6(1), 19–23 (2014).
  Google Scholar
• 88 Pazvantoglu O, Gunes S, Karabekiroglu K et al. The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample. Gene 528(2), 320–327 (2013).
  Medline CASGoogle Scholar
• 89 Hawi Z, Matthews N, Wagner J et al. DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex. PLoS ONE 8(4), e60274 (2013).
  Medline CASGoogle Scholar
• 90 Forero DA, Arboleda GH, Vasquez R, Arboleda H. Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants. J. Psychiatry Neurosci. 34(5), 361–366 (2009).
  MedlineGoogle Scholar
• 91 Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum. Genet. 126(1), 51–90 (2009).
  Medline CASGoogle Scholar
• 92 Oner O, Akin A, Herken H et al. Association among SNAP-25 gene DdeI and MnlI polymorphisms and hemodynamic changes during methylphenidate use: a functional near-infrared spectroscopy study. J. Atten. Disord. 15(8), 628–637 (2011).
  MedlineGoogle Scholar
• 93 Fisher RA. The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edin. 52, 399–433 (1918).
  Google Scholar
• 94 Cordell HJ. Detecting gene–gene interactions that underlie human diseases. Nat. Rev. Genet. 10(6), 392–404 (2009).
  Medline CASGoogle Scholar
• 95 Kang E, Burdick KE, Kim JY et al. Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. Neuron 72(4), 559–571 (2011).
  Medline CASGoogle Scholar
• 96 Sullivan D, Pinsonneault JK, Papp AC et al. Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene–gene–environment interaction. Transl. Psychiatry 3, e222 (2013).
  Medline CASGoogle Scholar
• 97 Lohoff FW, Narasimhan S, Rickels K. Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics J. 13(5), 464–469 (2013).
  Medline CASGoogle Scholar
• 98 Goncalves VF, Zai CC, Tiwari AK et al. A hypothesis driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 39(6), 1347–1354 (2013).
  Google Scholar
• 99 Ryu S, Oh S, Cho EY et al. Interaction between genetic variants of DLGAP3 and SLC1A1 affecting the risk of atypical antipsychotics-induced obsessive-compulsive symptoms. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B(8), 949–959 (2011).
  MedlineGoogle Scholar
• 100 Hwang R, Souza RP, Tiwari AK et al. Gene–gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics 12(2), 277–291 (2011).
  CASGoogle Scholar
• 101 Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl Acad. Sci. USA 109(4), 1193–1198 (2012).
  Medline CASGoogle Scholar
• 102 Jain M, Velez JI, Acosta MT et al. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Mol. Psychiatry 17(7), 741–747 (2012).
  Medline CASGoogle Scholar
• 103 Hong SB, Kim JW, Cho SC, Shin MS, Kim BN, Yoo HJ. Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction? J. Child. Adolesc. Psychopharmacol. 22(5), 343–352 (2012).
  Medline CASGoogle Scholar
• 104 Seeger G, Schloss P, Schmidt MH. Marker gene polymorphisms in hyperkinetic disorder – predictors of clinical response to treatment with methylphenidate? Neurosci. Lett. 313(1–2), 45–48 (2001).
  Medline CASGoogle Scholar
• 105 Rovaris DL, Mota NR, Callegari-Jacques SM, Bau CH. Approaching “phantom heritability” in psychiatry by hypothesis-driven gene–gene interactions. Front. Hum. Neurosci. 7, 210 (2013).
  MedlineGoogle Scholar
• 106 Wang X, Elston RC, Zhu X. The meaning of interaction. Hum. Hered. 70(4), 269–277 (2010).
  MedlineGoogle Scholar
• 107 Cumberworth A, Lamour G, Babu MM, Gsponer J. Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes. Biochem. J. 454(3), 361–369 (2013).
  Medline CASGoogle Scholar
• 108 Bolan EA, Kivell B, Jaligam V et al. D2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism. Mol. Pharmacol. 71(5), 1222–1232 (2007).
  Medline CASGoogle Scholar
• 109 Lee FJ, Pei L, Moszczynska A, Vukusic B, Fletcher PJ, Liu F. Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor. EMBO J. 26(8), 2127–2136 (2007).
  Medline CASGoogle Scholar
• 110 Bertolino A, Fazio L, Di Giorgio A et al. Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans. J. Neurosci. 29(4), 1224–1234 (2009).
  Medline CASGoogle Scholar
• 111 Gonzalez S, Rangel-Barajas C, Peper M et al. Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain. Mol. Psychiatry 17(6), 650–662 (2012).
  Medline CASGoogle Scholar
• 112 Borroto-Escuela DO, Van Craenenbroeck K, Romero-Fernandez W et al. Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions. Biochem. Biophys. Res. Commun. 404(4), 928–934 (2011).
  Medline CASGoogle Scholar
• 113 Mota NR, Rovaris DL, Bertuzzi GP et al. DRD2/DRD4 heteromerization may influence genetic susceptibility to alcohol dependence. Mol. Psychiatry 18(4), 401–402 (2013).
  Medline CASGoogle Scholar
• 114 Mota NR, Bau CH, Banaschewski T et al. Association between DRD2/DRD4 interaction and conduct disorder: a potential developmental pathway to alcohol dependence. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B(6), 546–549 (2013).
  MedlineGoogle Scholar
• 115 Munafo MR, Matheson IJ, Flint J. Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case–control studies and evidence of publication bias. Mol. Psychiatry 12(5), 454–461 (2007).
  Medline CASGoogle Scholar
• 116 Wang F, Simen A, Arias A, Lu QW, Zhang H. A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence. Hum. Genet. 132(3), 347–358 (2013).
  Medline CASGoogle Scholar
• 117 Bobadilla L, Vaske J, Asberg K. Dopamine receptor (D4) polymorphism is related to comorbidity between marijuana abuse and depression. Addict. Behav. 38(10), 2555–2562 (2013).
  MedlineGoogle Scholar
• 118 Usiello A, Baik JH, Rouge-Pont F et al. Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408(6809), 199–203 (2000).
  Medline CASGoogle Scholar
• 119 Zhang Y, Bertolino A, Fazio L et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc. Natl Acad Sci. USA 104(51), 20552–20557 (2007).
  Medline CASGoogle Scholar
• 120 Yang L, Neale BM, Liu L et al. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B(5), 419–430 (2013).
  MedlineGoogle Scholar
• 121 Ebejer JL, Duffy DL, Van Der Werf J et al. Genome-wide association study of inattention and hyperactivity-impulsivity measured as quantitative traits. Twin. Res. Hum. Genet. 16(2), 560–574 (2013).
  MedlineGoogle Scholar
• 122 Stergiakouli E, Hamshere M, Holmans P et al. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am. J. Psychiatry 169(2), 186–194 (2012).
  MedlineGoogle Scholar
• 123 Hinney A, Scherag A, Jarick I et al. Genome-wide association study in German patients with attention deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B(8), 888–897 (2011).
  MedlineGoogle Scholar
• 124 Fliers EA, Vasquez AA, Poelmans G et al. Genome-wide association study of motor coordination problems in ADHD identifies genes for brain and muscle function. World J. Biol. Psychiatry 13(3), 211–222 (2012).
  MedlineGoogle Scholar
• 125 Neale BM, Medland S, Ripke S et al. Case–control genome-wide association study of attention-deficit/hyperactivity disorder. J. Am. Acad. Child. Adolesc. Psychiatry 49(9), 906–920 (2010).
  MedlineGoogle Scholar
• 126 Neale BM, Medland SE, Ripke S et al. Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J. Am. Acad. Child. Adolesc. Psychiatry 49(9), 884–897 (2010).
  MedlineGoogle Scholar
• 127 Mick E, Todorov A, Smalley S et al. Family-based genome-wide association scan of attention-deficit/hyperactivity disorder. J. Am. Acad. Child. Adolesc. Psychiatry 49(9), 898–905e.3 (2010).
  MedlineGoogle Scholar
• 128 Neale BM, Lasky-Su J, Anney R et al. Genome-wide association scan of attention deficit hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(8), 1337–1344 (2008).
  Medline CASGoogle Scholar
• 129 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. 147B(8), 1412–1418 (2008).
  Medline CASGoogle Scholar
• 130 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 35(2), 466–472 (2011).
  Medline CASGoogle Scholar
• 131 Lango Allen H, Estrada K, Lettre G et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467(7317), 832–838 (2010).
  Medline CASGoogle Scholar
• 132 Teslovich TM, Musunuru K, Smith AV et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466(7307), 707–713 (2010).
  Medline CASGoogle Scholar
• 133 Michailidou K, Hall P, Gonzalez-Neira A et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat. Genet. 45(4), 353–361, 361e1–2 (2013).
  Medline CASGoogle Scholar
• 134 Eeles RA, Olama AA, Benlloch S et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45(4), 385–391, 391e381–2 (2013).
  Medline CASGoogle Scholar
• 135 Ripke S, O'Dushlaine C, Chambert K et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45(10), 1150–1159 (2013).
  Medline CASGoogle Scholar
• 136 IMpACT: International Multi-centre persistent ADHD CollaboraTion. www.impactadhdgenomics.com
  Google Scholar
• 137 Biederman J, Seidman LJ, Petty CR et al. Effects of stimulant medication on neuropsychological functioning in young adults with attention-deficit/hyperactivity disorder. J. Clin. Psychiatry 69(7), 1150–1156 (2008)
  MedlineGoogle Scholar
• 138 Brown TE, Brams M, Gao J, Gasior M, Childress A. Open-label administration of lisdexamfetamine dimesylate improves executive function impairments and symptoms of attention-deficit/hyperactivity disorder in adults. Postgrad. Med. 122(5), 7–17 (2010).
  MedlineGoogle Scholar
• 139 Brown TE, Holdnack J, Saylor K et al. Effect of atomoxetine on executive function impairments in adults with ADHD. J. Atten. Disord. 15(2), 130–138 (2011).
  MedlineGoogle Scholar
• 140 Fallu A, Richard C, Prinzo R, Binder C. Does OROS-methylphenidate improve core symptoms and deficits in executive function? Results of an open-label trial in adults with attention deficit hyperactivity disorder. Curr .Med. Res. Opin. 22(12), 2557–2566 (2006).
  Medline CASGoogle Scholar
• 141 Spencer TJ, Adler LA, Weisler RH, Youcha SH. Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: a randomized, double-blind, multicenter, placebo-controlled study. J. Clin. Psychiatry 69(9), 1437–1448 (2008).
  Medline CASGoogle Scholar
• 142 Brown TE, Brams M, Gasior M et al. Clinical utility of ADHD symptom thresholds to assess normalization of executive function with lisdexamfetamine dimesylate treatment in adults. Curr. Med. Res. Opin. 27(Suppl. 2), 23–33 (2011).
  MedlineGoogle Scholar
• 143 Yang L, Qian Q, Liu L, Li H, Faraone SV, Wang Y. Adrenergic neurotransmitter system transporter and receptor genes associated with atomoxetine response in attention-deficit hyperactivity disorder children. J. Neural. Transm. 120(7), 1127–1133 (2013).
  Medline CASGoogle Scholar
• 144 Ramoz N, Boni C, Downing AM et al. A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 34(9), 2135–2142 (2009).
  Medline CASGoogle Scholar
• 145 Matsui A, Azuma J, Witcher JW et al. Pharmacokinetics, safety, and tolerability of atomoxetine and effect of CYP2D6*10/*10 genotype in healthy Japanese men. J. Clin. Pharmacol. 52(3), 388–403 (2012).
  Medline CASGoogle Scholar
• 146 Bruxel EM, Akutagava-Martins GC, Salatino-Oliveira A et al. ADHD pharmacogenetics across the life cycle: new findings and perspectives. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165B(4), 263–282 (2014).
  MedlineGoogle Scholar
• 147 Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics 11(3), 407–419 (2010).
  CASGoogle Scholar
• 148 Polanczyk G, Bigarella MP, Hutz MH, Rohde LA. Pharmacogenetic approach for a better drug treatment in children. Curr. Pharm. Des. 16(22), 2462–2473 (2010).
  Medline CASGoogle Scholar
• 149 Marshall SL, Guennel T, Kohler J, Man M, Fossceco S. Estimating heritability in pharmacogenetic studies. Pharmacogenomics 14(4), 369–377 (2013).
  CASGoogle Scholar
• 150 McGeachie MJ, Stahl EA, Himes BE et al. Polygenic heritability estimates in pharmacogenetics: focus on asthma and related phenotypes. Pharmacogenet. Genomics 23(6), 324–328 (2013).
  Medline CASGoogle Scholar
• 151 Song K, Mosteller M, Lawson M, Nelson MR. Practical limitations to estimating heritability in pharmacogenetic studies. Pharmacogenomics 14(8), 851–852 (2013).
  CASGoogle Scholar
• 152 Gamazon ER, Perera M. Genome-wide approaches in pharmacogenomics: heritability estimation and pharmacoethnicity as primary challenges. Pharmacogenomics 13(10), 1101–1104 (2012).
  CASGoogle Scholar
• 153 Marchant BK, Reimherr FW, Robison RJ, Olsen JL, Kondo DG. Methylphenidate transdermal system in adult ADHD and impact on emotional and oppositional symptoms. J. Atten. Disord. 15(4), 295–304 (2011).
  MedlineGoogle Scholar
• 154 Reimherr FW, Williams ED, Strong RE, Mestas R, Soni P, Marchant BK. A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J. Clin. Psychiatry 68(1), 93–101 (2007).
  Medline CASGoogle Scholar
• 155 Schubiner H, Saules KK, Arfken CL et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp. Clin. Psychopharmacol. 10(3), 286–294 (2002).
  Medline CASGoogle Scholar
• 156 Carpentier PJ, De Jong CA, Dijkstra BA, Verbrugge CA, Krabbe PF. A controlled trial of methylphenidate in adults with attention deficit/hyperactivity disorder and substance use disorders. Addiction 100(12), 1868–1874 (2005).
  MedlineGoogle Scholar
• 157 Levin FR, Evans SM, Brooks DJ, Kalbag AS, Garawi F, Nunes EV. Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo. Drug Alcohol Depend. 81(2), 137–148 (2006).
  Medline CASGoogle Scholar
• 158 Levin FR, Evans SM, Brooks DJ, Garawi F. Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug Alcohol Depend. 87(1), 20–29 (2007).
  Medline CASGoogle Scholar
• 159 Biederman J, Mick E, Spencer T, Surman C, Faraone SV. Is response to OROS-methylphenidate treatment moderated by treatment with antidepressants or psychiatric comorbidity? A secondary analysis from a large randomized double blind study of adults with ADHD. CNS Neurosci. Ther. 18(2), 126–132 (2012).
  Medline CASGoogle Scholar
• 160 Marchant BK, Reimherr FW, Halls C, Williams ED, Strong RE. OROS methylphenidate in the treatment of adults with ADHD: a 6-month, open-label, follow-up study. Ann. Clin. Psychiatry 22(3), 196–204 (2010).
  MedlineGoogle Scholar
• 161 Robison RJ, Reimherr FW, Gale PD et al. Personality disorders in ADHD part 2: the effect of symptoms of personality disorder on response to treatment with OROS methylphenidate in adults with ADHD. Ann. Clin. Psychiatry 22(2), 94–102 (2010).
  MedlineGoogle Scholar
• 162 Chazan R, Borowski C, Pianca T, Ludwig H, Rohde LA, Polanczyk G. Do phenotypic characteristics, parental psychopathology, family functioning, and environmental stressors have a role in the response to methylphenidate in children with attention-deficit/hyperactivity disorder? A naturalistic study from a developing country. J. Clin. Psychopharmacol. 31(3), 309–317 (2011).
  Medline CASGoogle Scholar
• 163 Murray DW, Arnold LE, Swanson J et al. A clinical review of outcomes of the multimodal treatment study of children with attention-deficit/hyperactivity disorder (MTA). Curr. Psychiatry Rep. 10(5), 424–431 (2008).
  MedlineGoogle Scholar
• 164 Rubio B, Hernandez S, Verche E, Martin R, Gonzalez-Perez P. A pilot study: differential effects of methylphenidate-OROS on working memory and attention functions in children with attention-deficit/hyperactivity disorder with and without behavioural comorbidities. Atten. Defic. Hyperact. Disord. 3(1), 13–20 (2011).
  MedlineGoogle Scholar
• 165 Park S, Kim BN, Cho SC et al. Baseline severity of parent-perceived inattentiveness is predictive of the difference between subjective and objective methylphenidate responses in children with attention-deficit/hyperactivity disorder. J. Child. Adolesc. Psychopharmacol. 23(6), 410–414 (2013).
  Medline CASGoogle Scholar
• 166 Newcorn JH, Stein MA, Cooper KM. Dose-response characteristics in adolescents with attention-deficit/hyperactivity disorder treated with OROS methylphenidate in a 4-week, open-label, dose-titration study. J. Child. Adolesc. Psychopharmacol. 20(3), 187–196 (2010).
  MedlineGoogle Scholar
• 167 Polanczyk G, De Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am. J. Psychiatry 164(6), 942–948 (2007).
  MedlineGoogle Scholar
• 168 Simon V, Czobor P, Balint S, Meszaros A, Bitter I. Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br. J. Psychiatry 194(3), 204–211 (2009).
  MedlineGoogle Scholar
• 169 Klein RG, Mannuzza S, Olazagasti MA et al. Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later. Arch. Gen. Psychiatry 69(12), 1295–1303 (2012).
  MedlineGoogle Scholar
• 170 McGough JJ, Smalley SL, McCracken JT et al. Psychiatric comorbidity in adult attention deficit hyperactivity disorder: findings from multiplex families. Am. J. Psychiatry 162(9), 1621–1627 (2005).
  MedlineGoogle Scholar
• 171 Purper-Ouakil D, Wohl M, Orejarena S et al. Pharmacogenetics of methylphenidate response in attention deficit/hyperactivity disorder: association with the dopamine transporter gene (SLC6A3). Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(8), 1425–1430 (2008).
  Medline CASGoogle Scholar
• 172 Kambeitz J, Romanos M, Ettinger U. Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD. Pharmacogenomics J. 14(1), 77–84 (2014).
  Medline CASGoogle Scholar