Candidate Gene Studies of Attention Deficit Hyperactivity Disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric condition that affects approximately 5-10% of children worldwide. This disorder is defined by a combination of symptoms of inattention and hyperactivity/impulsivity. Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. Molecular genetic studies support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. This article reviews the latest findings on the molecular genetics of ADHD.

Keywords

• ADHD, genetics, candidate gene studies, etiology

Dikkat Eksikliği Hiperaktivite Bozukluğunda Aday Gen Çalışmaları

Öz

Dikkat eksikliği hiperaktivite bozukluğu (DEHB) çocuklarda %5-10 oranında görülen yaygın bir psikiyatrik rahatsızlıktır. Bu hastalık dikkat eksikliği ve hiperaktivite/dürtüsellik belirtilerinin bileşimi olarak tanımlanmıştır. İkiz çalışmalarında DEHB'nin yüksek derecede kalıtılabirliğinin kanıtlanmış, yapılan moleküler genetik çalışmalarda da DEHB'de karmaşık bir genetik yapı olduğu tespit edilmiştir. Moleküler genetik çalışmalar, bu kompleks hastalığın etyolojisinde dopaminerjik, serotonerjik ve noradrenerjik nörotransmisyondaki sorunlardan kaynaklandığını göstermektedir. Bu çalışmada DEHB'nin moleküler genetiği ile ilgili en son bulgular kapsamlı olarak gözden geçirilmiştir. Anahtar Sözcükler:

Anahtar Kelimeler

• DEHB, genetik, aday gen çalışmaları, etyoloji

References

1. Schwab-Stone M. Epidemiology of ADHD in school-age children. Child Adolesc Psychiatr Clin N Am 2000; 9:541-555.
2. Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006; 163:716–723.
3. Akgün GM, Tufan E, Yurteri N, Erdogan A. Dikkat Eksikliği Hiperaktivite Bozuklu- ğunun Genetik Boyutu. Psikiyatride Güncel Yaklaşımlar 2011; 3:15-48.
4. Hecthman L. Attention deficit hyperactivity disorder. In Comprehensive Textbook of Psychiatry, 8th edition (Eds BJ Saddock, VA Saddock):2679-2692. Philadelphia, Lippincott Williams & Wilkins, 2005.
5. Perlov E, Philipsen A, Hesslinger B, Buechert M, Ahrendts J, Feige B et al. Reduced cingulated glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder- A magnet resonance spectroscopy study. J Psychiatr Res 2007; 41:934-941.
6. Rohde LA, Halpern R. Recent advances on attention deficit/hyperactivity disorder. Journal de Pediatria 2004; 80:61-70.
7. Thapar A, Holmes J, Poulton K, Harreington R. Genetic basis of attention deficit and hyperactivity. Br J Psychiatry 1999; 174:105-111.
8. Faraone SV, Biederman J. Nature, nurture and attention deficit hyperactivity disorder. Dev Rev 2000; 20:568-581.

9. Rietveld MJ, Hudziak JJ, Bartels M, van Beijsterveldt CE, Boomsma DI. Heritability of attention problems in children: I. Cross-sectional results from a study of twins, age 3-12 years. Am J Med Genet B Neuropsychiatr Genet 2003; 117B:102-113.
10. Bobb AJ, Castellanos FX, Addington AM, Rapoport JL. Molecular genetic studies of ADHD:1991 to 2004. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:551- 565.
11. Comings DE, Comings BG, Muhleman D, Dietz G, Shahbahrami B, Tast D et al. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 1991; 266:1793-1800.
12. Rowe DC, den Oord EJ, Stever C, Giedinghagen LN, Gard JM, Cleveland HH et al. The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder. Mol Psychiatry 1999; 4:580-586.
13. Retz W, Rosler M, Supprian T, Retz-Junginger P, Thome J. Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD- related psychopathology. J Neural Transm 2003; 110:561-572.
14. Xu M, Koeltzow TE, Santiago GT, Moratalla R, Cooper DC, Hu XT et al. Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron 1997; 19:837-848.
15. Payton A, Holmes J, Barrett JH, Hever T, Fitzpatrick H, Trumper AL et al. Examining for association between candidate gene polymorphisms in the dopamine pathway and attentiondeficit hyperactivity disorder: a family-based study. Am J Med Genet 2001; 105:464-470.
16. Muglia P, Jain U, Kennedy JL. A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder. Behav Brain Res 2002; 130:91–95.
17. Thapar A, O’Donovan M, Owen MJ. The genetics of attention deficit hyperactivity disorder. Human Mol Genet 2005; 14:275-282.
18. Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O et al. Multiple dopamine D4 receptor variants in the human population. Nature 1992; 358:149- 152.
19. Oak JN, Oldenhof J, Van Tol HH. The dopamine D(4) receptor: One decade of research. Eur J Pharmacol 2000; 405:303-327.
20. Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D et al. Polymorphisms of the dopamine d4 receptor, clinical outcome and cortical structure in attention deficit/hyperactivity disorder. Arch Gen Psychiatry 2007; 64:921-931.
21. Sevinc E, Erdal ME, Sengul C, Cakaloz B, Ergundu TG, Herken H. Association of adult attention deficit hyperactivity disorder with dopamine transporter gene, dopamine D3 receptor, and dopamine D4 receptor gene polymorphisms. Klinik Psikofarmakoloji Bülteni 2010; 20:196-203.
22. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK. The worlwide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 1996; 98:91-101.
23. Qian Q, Wang Y, Zhou R, Yang L, Faraone SV. Family-based and case control association studies of DRD4 and DAT1 polymorphisms in Chinese attention deficit hyperactivity disorder patients suggest long repeats contribute to genetic risk for the disorder. Am J Med Genet B Neuropsychiatr Genet 2004; 128B:84-89.
24. Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL et al. The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 2004; 74:931-944.
25. Holmes J, Payton A, Barrett J, Harrington R, McGuffinP, OwenM et al. Association of DRD4 in children with ADHD and comorbid conduct problems. Am J Med Genet 2002; 114:150-153.
26. Langley K, Fowler TA, Grady DL, Moyzis RK, Holmans PA, Van Den Bree MBM et al. Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 2009; 18:26-32.
27. Li D, Sham PC, Owen MJ, He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 2006; 15:2276-2284.
28. McGough J, McCracken J, Swanson J, Riddle M, Scott K, Greenhill L et al. Pharmacogenetics of methylphenidate response in preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry 2006; 45:1314-1322.
29. LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N et al. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1996; 1:121- 124.
30. Mill J, Caspi A, Williams BS, Craig I, Taylor A, Polo-Tomas M et al. Prediction of heterogeneity in ıntelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention- deficit/hyperactivity disorder. Arch Gen Psychiatry 2006; 63:462-469.
31. Daly G, Hawi Z, Fitzgerald M, Gill M. Mapping susceptibility loci in attention deficit hyperactivity disorder: Preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol Psychiatry 1999; 4:192-196.
32. Comings DE, Grade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Blake H et al. Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: Multivariate regression analysis of 20 genes. Clin Genet 2000; 57:178-196.
33. Yang B, Chan RCK, Jing J, Li T, Sham P, Chen YL. A meta analysis of association studied between the 10-repeat allele of a VNTR polymorphism in the 3’UTR of dopamine transporter gene and attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:541-550.
34. Cook EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, et al. Association of attention deficit disorder and the dopamine transporter gene. Am J Hum Genet 1995; 56:993-998.
35. Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M. Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry 1997; 2:311-313.
36. Asherson P, Virdee V, Curran S, Ebersole L, Freeman B, Craig I et al. Association study of DSM IV attention deficit hyperactivity disorder (ADHD) and monoamine pathway genes. Am J Med Genet 1998; 81:549.
37. Winsberg BG, Comings DE. Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 1999; 38:1474-1477.
38. Bellgrove MA, Hawi Z, Kirlye A,Gill M, Robertson IH. Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: Sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype. Neuropsychologia 2005; 43:1847-1857.
39. Barkley RA, Smith KM, Fischer M, Navia B. An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:487- 498.
40. Smith KM, Daly M, Fischer M, Yiannoutsos CT, Bauer L, Barkley R et al. Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: Genetic analysis of the Milwaukee longitudinal study. Am J Med Genet 2003; 119:77- 85.
41. Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH. Further evidence for the association between attention-deficit/hyperactivity disorder and the dopamine-beta-hydroxylase gene. Am J Med Genet 2002; 114:154-158.
42. Comings DE, Gade R, Muhleman D, Sverd J. No association of a tyrosine hydroxylase gene tetranucleotide repeat polymorphism in autism, Tourette syndrome, or ADHD. Biol Psychiatry 1995; 37:484-486.
43. Halperin JM, Newcorn JH, Schwartz ST, Sharma V, Siever LJ, Koda VH. Age related changes in the association between serotonin function and aggression in boys with ADHD. Biol Psychiatry 1997; 41:682-689.
44. Spivak B, Vered Y, Yoran-Hegesh R, Averbuch E, Mester R, Graf E et al. Circulatory levels of catecholamines, serotonin and lipids in attention deficit hyperactivity disorder. ActaPsychiatr Scand 1999; 99:300-304.
45. O’Neill MF, Heron-Maxwell CL, Shaw G. 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine and Mk-801 but not D1 agonist C- APB. Pharmacol Biochem Behav 1999; 63:237-243.
46. Kelland MD, Chiodo LA. Serotonergic modulation of midbrain dopamine systems. In The Modulation of Dopaminergic Neurotransmission by Other Neurotransmitters (Ed CR Ashby Jr.):87-112. Florida, CRC Press, 1996.
47. Hawi Z, Dring M, Kirley A, Foley D, Kent L, Craddock N et al. Serotonergic system and attention deficit hyperactivity disorder (ADHD): A potential susceptibility locus at the 5-HT 1B receptor gene in 273 nuclear families from a multi-centre sample. Mol Psychiatr 2002; 7:718-725.
48. Guimaraes APM, Zeni C, Polanczyk GV, Genro JP, Roman T, Rohde LA et al. Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: Preferential transmission of the HTR2A 452His allele to affected boys. Am J Med Genet B Neurospychiatr Genet 2007; 144B:69-73.
49. Zoroglu SS, Erdal ME, Erdal N, Ozen S, Alasehirli B, Sivasli E. No evidence for an association between the T102C and 1438 G/A polymorphisms of the serotonin 2A receptor gene in attention deficit/ hyperactivity disorder in a Turkish population. Neuropsychobiology 2003; 47:17-20.
50. Quist JF, Barr CL, Schachar R, Roberts W, MaloneM, Tannock R et al. Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 2000; 5:537-541.
51. Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK et al. Support for association between ADHD and two candidate genes: NET1 and DRD1 Am J Med Genet B Neuropsychiatr Genet 2005; 134:67-72.
52. Li J, Wang Y, Qian Q, Wang B, Zhou R. Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children. Zhonghua Yi Xue Za Zhi 2002; 82:1173-1176.
53. Reuter M, Kirsch P, Hennig J. Inferring candidate genes for attention deficit hyperactivity disorder (ADHD) assessed by the World Health Organization Adult ADHD Self-Report Scale (ASRS). J Neural Transm 2006; 113:929-938.
54. Turecki G, Briere R, Dewar K, Antonetti T, Lesage AD, Seguin M et al. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 1999; 156:1456–1458.
55. Brown GL, Linnoila MI. CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity and violence. J Clin Psychiatry 1990; 51:31-41.
56. Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R et al.The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry 2003; 8:98-102.
57. Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry 2001; 6:235-238.
58. Zoroglu SS, Erdal ME, Alasehirli B, Erdal N, Sivasli E, Tutkun H et al. Significance of serotonin transporter gene 5-HTTLPR and variable number of tandem repeat polymorphism in attention deficit hyperactivity disorder. Neuropsychobiology 2002;
59. Langley K, Payton A, Hamshere ML, Pay HM, Lawson DC, Turic D et al. No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder. Psychiatr Genet 2003; 13:107-110.
60. Mao ZM, Li BM, Arnsten AF. Roles of adrenoreceptor in prefrontal cortical cognitive functions. Sheng Li Ke Xue Jin Zhan 1999; 30:17-22.
61. Schmitz M, Denardin D, Silva TL, Pianca T, Roman T, Hutz MH et al. Association between alpha-2a-adrenergic receptor gene and ADHD inattentive type. Biol Psychiatry 2006; 60:1028-1033.
62. Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH. Is the alpha- 2A adrenergic receptor gene (ADRA2A) associated with attention- deficit/hyperactivity disorder? Am J Med Genet B Neuropsychiatr Genet 2003; 120:116-120.
63. Xu C, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL et al. Linkage study of the alpha2A adrenergic receptor in attention-deficit hyperactivity disorder families. Am J Med Genet 2001; 105:159 -162.
64. Park L, Nigg JT, Waldman ID, Nummy KA, Huang-Pollock C, Rappley M et al. Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Mol Psychiatry 2005; 10:572-580.
65. Wang B, Wang Y, Zhou R, Li J, Qian Q, Yang L et al. Possible association of the alpha-2A adrenergic receptor gene (ADRA2A) with symptoms of attention- deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:130-134.
66. 66. Stevenson J, Langley K, Pay H, Payton A, Worthington J, Ollier W et al. Attention deficit hyperactivity disorder with reading disabilities: preliminary genetic findings on the involvement of the ADRA2A gene. J Child Psychol and Psychiatr 2005; 46:1081-1088.
67. Polanczyk G, Zeni C, Genro JP, Guimaraes AP, Roman T, Hutz MH et al. Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention- deficit/hyperactivity disorder. Arch Gen Psychiatry 2007; 64:218-224.
68. Barr CL, Wigg K, Zai G, Roberts W, Malone M, Schachar R et al. Attention-deficit hyperactivity disorder and the adrenergic receptors alpha 1C and alpha 2C.Mol Psychiatry 2001; 6:334–337.
69. Comings D, Gade-Andavolu R, Gonzalez N, Blake H, MacMurray J. Additive effect of three noradenergic genes (ADRA2A, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clin Genet 1999; 55:160 -172.
70. De Luca V, Muglia P, Vincent JB, Lanktree M, Jain U, Kennedy JL. Adrenergic alpha 2C receptor genomic organization: association study in adult ADHD. Am J Med Genet B Neuropsychiatr Genet 2004; 127B:65-67.
71. Barr CL, Kroft J, Feng Y, Wigg K, Roberts W, Malone M et al. The norepinephrine transporter gene and attention-deficit hyperactivity disorder. Am J Med Genet 2002;
72. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6:243-250.
73. Eisenberg J, Mei-Tal G, Steinberg A, Tartakovsky E, Zohar A, Gritsenko I et al. Haplotype relative risk study of catechol- O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. Am J Med Genet 1999; 88:497- 502.
74. Manor I, Kotler M, Sever Y, Eisenberg J, Cohen H, Ebstein RP et al. Failure to replicate an association between the catechol-Omethyltransferase polymorphism and attention deficit hyperactivity disorder in a second, independently recruited Israeli cohort. Am J Med Genet 2000; 96:858-860.
75. Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention deficit hyperactivity disorder:a review and integration. Behav Brain Res 1998; 94:127-152.
76. Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF. A regulatory polymorphism of the monoamine oxidase A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity. Psychiatry Res 2000; 95:9-23.
77. Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA, Mixson AJ et al. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med 1993; 328:997-1001.
78. Hauser P, Soler R, Brucker-Davis F, Weintraub BD. Thyroid hormones correlate with symptoms of hyperactivity but not inattention in attention deficit hyperacitivity disorder. Psychoneuroendocrinology 1997; 22:107-114.
79. Weiss RE, Stein MA, Trommer B, Refetoff S. Attention-deficit hyperactivity disorder and thyroid function. J Pediatr 1993; 123:539-545.
80. Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen TT 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.
81. Aspide R, Fresiello A, de Filippis G, Gironi Carnevale UA, Sadile AG. Non-selective attention in a rat model of hyperactivity and attention deficit: subchronic methylphenydate and nitric oxide synthesis inhibitor treatment. Neurosci Biobehav Rev 2000; 24:59-71.
82. Reif A, Jacob CP, Rujescu D, Herterich S, Lang S, Gutknecht L, et al. Influence of functional variant of neuronal nitric oxide synthase on impulsive behaviors in humans. Arch Gen Psychiatry 2009; 66:41-50.
83. Ceylan M, Sener S, Cavunt A, Kavutcu M. Oxidative imbalance in child and adolescent patients with attention-deficit/hyperactivity disorder. Neuropsychopharmacol Biol Psychiatry 2010; 34:1491-1494. Prog