Dikkat Eksikliği Hiperaktivite Bozukluğu ve Genetik

Dikkat Eksikliği Hiperaktivite Bozukluğu (DEHB) üç temel özelliği çocukluk döneminde başlayan dikkatsizlik, gelişimsel düzeye uygun olmayan aşırı hareketlilik ve dürtüsellik olan nörogelişimsel bir bozukluktur. Dünya çapında yaygınlığı çocuklarda %5-12 ve yetişkinlerde %4.4 kadardır. DEHB hem birey hem de aile ve toplum açısından önemli sorunlara zemin hazırlamaktadır ve bu nedenle bozuk-luğun erken tanınması ve aynı zamanda bozukluğa yatkınlık oluşturan faktörlerin anlaşılması önemli-dir. DEHB, etyolojisinde genetik ve çevresel faktörlerin rol oynadığı multifaktöriyel bir bozukluktur. Yapılan tüm çalışmalar DEHB’nin kalıtılabilirlik oranının %76 gibi hayli yüksek bir oranda olduğunu göstermiştir. Bu yazıda DEHB genetiği ikiz çalışmaları, evlat edinme çalışmaları, aile çalışmaları, segregasyon analizleri ve moleküler genetik çalışmalar şeklinde sınıflandırılarak anlatılmış ve DEHB’nin genetik yönünün gözden geçirilmesi amaçlanmıştır.

Anahtar Kelimeler:

Genetik, dikkat eksikliği hiperaktivite bozukluğu, dopamin

Attention Deficit Hyperactivity Disorder and Genetics

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder of which three basic symptoms are lack of attention, over-activity that is improper to the age and impulsivity, all of which appear in childhood. Its incidence is %5-12 in children and %4.4 in adults throughout the world. ADHD provides a basis for important problems for both patient, family and society and thus it is important to diagnose the disorder early and understand the factors that create predisposition to the disorder. ADHD is a multifactorial disorder with an etiology of genetic and environmental com-ponents. The importance of genetic factors first implied by Cantwell and Morrison is supported by many studies ever since. All these studies showed that inheritance rate of ADHD is as high as %76. The aim of this article is to explain ADHD genetics in categorization of twin studies, adoption studies, family studies, segregation analyzes and molecular genetic researches and to review the genetic component of ADHD.

Keywords:

Genetics, attention deficit hyperactivity disorder, dopamine,

PDF

___

Akgün GM, Tufan E, Yurteri N, Erdoğan A (2011) Dikkat eksikliği hiperaktivite bozukluğunun genetik boyutu. Psikiyatride Guncel Yaklasimlar-Current Approaches in Psychiatry, 3:15-48.
Aktepe E (2011). Dikkat eksikliği hiperaktivite bozukluklğu tanısı konan çocuk ve ergenlerde eş tanılar ve sosyodemografik özellikler. Yeni Symposium, 49:201-208.
Alberts-Corush J, Firestone P, Goodman JT (1986). Attention and impulsivity characteristics of the biological and adoptive parents of hyperactive and normal control children. Am J Orthopsychiatry, 56:413-423.
Aoki C, Go C-G, Venkatesan C, Kurose H (1994) Perikaryal and synaptic localization ofα 2A-adrenergic receptor-like immunoreactivity. Brain Res, 650:181-204.
Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG et al. (2004) Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13. 2, 5q33. 3, 11q22, and 17p11. Am J Hum Genet, 75:998-1014.
Arnsten A (2005) Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry, 67:7-12.
Asherson P, Consortium I (2004) Attention–deficit hyperactivity disorder in the post–genomic era. Eur Child Adolesc Psychiatry, 13:i50-i70.
Asherson P, Zhou K, Anney RJ, Franke B, Buitelaar J, Ebstein R et al.(2008) A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16. Mol Psychiatry, 13:514-521.
Asherson PJ, Curran S (2001) Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology. Br J Psychiatry, 179:122-128.
APA (American Psychiatric Association) (2013) Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5). Washington DC, American Psychiatric Association.
Aydın H, Diler RS, Yurdagül E, Uğuz Ş, Şeydaoğlu G (2006) DEHB tanılı çocukların ebeveynlerinde DEHB oranı. Klinik Psikiyatri Dergisi, 9:70-74.
Bacanlı A (2011) Dikkat eksikliği hiperaktivite bozukluğu ile dopamin reseptör 4 ve dopamin taşıyıcı gen polimorfizmlerinin ilişkisi (Uzmanlık Tezi). İzmir, Ege Üniversitesi.
Bakker S, Van der Meulen E, Buitelaar J, Sandkuijl L, Pauls D et al. (2003) A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet, 72:1251-1260.
Banaschewski T, Becker K, Scherag S, Franke B, Coghill D (2010) Molecular genetics of attention-deficit/hyperactivity disorder: an overview. Eur Child Adolesc Psychiatry, 19:237-257.
Barkley RA, Smith KM, Fischer M, Navia B (2006) 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, 141:487-498.
Barr CL, Kroft J, Feng Y, Wigg K, Roberts W, Malone M et al (2002) The norepinephrine transporter gene and attention‐deficit hyperactivity disorder. Am J Med Genet A, 114:255-259.
Bidwell LC, Willcutt EG, DeFries JC, Pennington BF (2007) Testing for neuropsychological endophenotypes in siblings discordant for attention-deficit/hyperactivity disorder. Biol Psychiatry, 62:991-998.
Bidwell LC, Dew RE, Kollins SH (2010) Alpha-2 adrenergic receptors and attention-deficit/hyperactivity disorder. Curr Psychiatry Rep, 12:366-373.
Biederman J, Faraone SV, Keenan K, Steingard R, Tsuang MT (1991) Familial association between attention deficit disorder and anxiety disorders. Am J Psychiatry, 148:251-256.
Biederman J, Spencer T (1999) Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry, 46:1234-1242.
Biederman J, Kim JW, Doyle AE, Mick E, Fagerness J, Smoller JW et al. (2008) 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, 147:1511-1518.
Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK et al.(2005) Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet, 134:67-72.
Bono M, Cases A, Oriola J, Calls J, Torras A, Rivera F (1996) Polymorphisms of the human alpha 2A-adrenergic receptor gene in a Catalan population: description of a new polymorphism in the promoter region. Gene Geogr, 10:151-159.
Bowden CL, Deutsch CK, Swanson JM (1988) Plasma dopamine-β-hydroxylase and platelet monoamine oxidase in attention deficit disorder and conduct disorder. J Am Acad Child Adolesc Psychiatry, 27:171-174.
Brookes K, Mill J, Guindalini C, Curran S, Xu X, Knight J et al. (2006a) A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy. Arch Gen Psychiatry, 63:74-81.
Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N et al. (2006b) 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, 11:934-953.
Bruno KJ, Freet CS, Twining RC, Egami K, Grigson PS, Hess EJ (2007) Abnormal latent inhibition and impulsivity in coloboma mice, a model of ADHD. Neurobiol Dis, 25:206-216.
Caballero J, Nahata MC (2003) Atomoxetine hydrochloride for the treatment of attention-deficit/hyperactivity disorder. Clin Ther, 25:3065-3083.
Cantwell DP (1972) Psychiatric illness in the families of hyperactive children. Arch Gen Psychiatry, 27:414-417.
Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nature Rev Neurosci, 3:617-628.
Comings DE, Wu S, Chiu C, Ring RH, Gade R, Ahn C et al. (1996) Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes—DRD2, DβH, and DAT1. Am J Med Genet, 67:264-288.
Cook Jr EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE et al.(1995) Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet, 56:993-998.
Craig S, Buckle V, Lamouroux A, Mallet J, Craig I (1988) Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34. Cytogenet Cell Genet, 48:48-50.
Curran S, Mill J, Tahir E, Kent L, Richards S, Gould A et al. (2001) Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples. Mol Psychiatry, 6:425-428.
Çetin FH, Taş Torun Y, Işık Taner Y (2015) Atomoxetine versus OROS methylphenidate in attention deficit hyperactivity disorder: asix-month follow up study for efficacy and adverse effects. Turkiye Klinikleri Journal of Medical Sciences, 35:88-96.
Deutsch CK, Matthysse S, Swanson JM, Farkas LG (1990) Genetic latent structure analysis of dysmorphology in attention deficit disorder. J Am Acad Child Adolesc Psychiatry, 29:189-194.
Doucette‐Stamm LA, Blakely DJ, Tian J, Mockus S, Mao Ji (1995) Population genetic study of the human dopamine transporter gene (DAT1). Genet Epidemiol 12:303-308
Durston S, Zeeuw P, Staal WG (2009) Imaging genetics in ADHD: a focus on cognitive control. Neuroscience Biobehav Rev, 33:674–689.
Durston S (2010) Imaging genetics in ADHD. Neuroimage, 53:832-838.
Dwivedi Y, Pandey GN (1998) Quantitation of 5HT2A receptor mRNA in human postmortem brain using competitive RT‐PCR. Neuroreport, 9:3761-3765.
Edelbrock C, Rende R, Plomin R, Thompson LA (1995) A twin study of competence and problem behavior in childhood and early adolescence. J Child Psychol Psychiatry, 36:775-785.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112:257–269.
Ercan ES, Turgay A (1998) Dikkat eksikliği hiperaktivite bozukluğunun etyolojisinde genetik etmenler. Çocuk ve Gençlik Ruh Sağlığı Dergisi, 5:160-169.
Ercan ES (2010) Dikkat eksikliği hiperaktivite bozukluğunda epidemiyolojik veriler. Turkiye Klinikleri Journal of Pediatric Sciences, 6:1-5.
Faraone SV, Biederman J, Chen WJ, Krifcher B, Keenan K, Moore C et al. (1992) Segregation analysis of attention deficit hyperactivity disorder. Psychiatr Genet, 2:257-276.
Faraone SV, Biederman J, Weiffenbach B, Keith T, Chu MP, Weaver A et al. (1999). Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am J Psychiatry, 156:768-770.
Faraone SV, Biederman J (2000) Nature, nurture, and attention deficit hyperactivity disorder. Dev Rev, 20:568-581.
Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA et al. (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry, 57:1313-1323.
Faraone SV, Doyle AE, Lasky-Su J, Sklar PB, D'Angelo E, Gonzalez Heydrich J et al. (2008) Linkage analysis of attention deficit hyperactivity disorder. Am J Medic Genet B Neuropsychiatr Genet, 147:1387-1391.
Faraone SV, Mick E (2010) Molecular genetics of attention deficit hyperactivity disorder. Psychiatr Clin North Am, 33:159-180.
Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL et al. (2002) A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet, 70:1183-1196.
Franke B, Neale BM, Faraone SV (2009) Genome-wide association studies in ADHD. Hum Genet, 126:13-50.
Gainetdinov RR (2010) Strengths and limitations of genetic models of ADHD. Atten Defic Hyperact Disord, 2:21-30.
Gelernter J, Kennedy J, Van Tol H, Civelli O, Kidd K (1992) The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Genomics, 13:208-210.
Gelernter J, Kruger S, Pakstis AJ, Pacholczyk T, Sparkes RS, Kidd KK et al. (1993) Assignment of the norepinephrine transporter protein (NET1) locusto chromosome 16. Genomics, 18:690-692.
Gelernter J, Pakstis A, Kidd K (1995) Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17. Hum Genet, 95:677-680.
Gilger JW, Pennington BF, DeFries JC (1992) A twin study of the etiology of comorbidity: attention-deficit hyperactivity disorder and dyslexia. J Am Acad Child Adolesc Psychiatry, 31:343-348.
Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet, 126:51-90.
Güçlü O, Erkıran M (2004) Dikkat eksikliği hiperaktivite bozukluğu tanısı konmuş çocukların ebeveynlerinde psikiyatrik yüklülük. Klinik Psikiyatri Dergisi, 7:32-41.
Güney E, Ceylan MF, İşeri E (2011) Dikkat eksikliği hiperaktivite bozukluğunda aday gen çalışmaları. Psikiyatride Güncel Yaklasimlar-Current Approaches in Psychiatry, 3:664-682.
Güney E, Iseri E, Ergun SG, Percin EF, Ergun MA, Yalcin O et al. (2014) T102C and 1438 G/A polymorphisms of the serotonin 2A receptor gene in etiology and course of ADHD. Int J Hum Genet, 14:59-66.
Gürsoy T (2010) Dikkat eksikliği ve hiperaktivite bozukluğu olan çocuklarda katekol-O metiltransferaz gen polimorfizminin araştırılması (Uzmanlık tezi). Edirne, Trakya Üniversitesi.
Hall FS, Drgonova J, Goeb M, Uhl GR (2003) Reduced behavioral efects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuropsychopharmacology, 28:1485–1490.
Hawi Z, Matthews N, Barry E, Kirley A, Wagner J, Wallace RH et al. (2013) A high density linkage disequilibrium mapping in 14 noradrenergic genes: evidence of association between SLC6A2, ADRA1B and ADHD. Psychopharmacology, 225:895-902.
Hebebrand J, Dempfle A, Saar K, Thiele H, Herpertz-Dahlmann B, Linder M et al. (2006) A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Mol Psychiatry, 11:196-205.
Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D et al. (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem, 66:2621-2624.
Hess E, Jinnah H, Kozak C, Wilson M (1992) Spontaneous locomotor hyperactivity in a mouse mutant with a deletion including the Snap gene on chromosome 2. J Neurosci, 12:2865-2874.
Hergüner S, Hergüner A (2012) Dikkat eksikliği hiperaktivite bozukluğu olan çocuk ve ergenlerde eşlik eden psikiyatrik bozukluklar. Noro Psikiyatr Ars, 49:114-118.
Herken H, Erdal E, Şengül C, Yücel E, Çakaloz B, Kenar Aİ et al. (2009) Erişkin dikkat eksikliği hiperaktivite bozukluğu ile sinaptozomla ilişkili protein (Snap-25) gen polimorfizmi ilişkisi. Klinik Psikofarmakol Bülteni, 19:142-143.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nature Genet, 29:306-309.
İmren GS (2010) Dikkat eksikliği hiperaktivite bozukluğu (DEHB) olan çocuk ve ergenlerin kardeşlerinde DEHB belirtileri,duygusal, davranışsal sorunlar ve psikopatoloji (Uzmanlık tezi). İstanbul, Marmara Üniversitesi.
İnci Kenar AN (2011) Erişkin dikkat eksikliği hiperaktivite bozukluğunun VAMP-2, sinapsin III ve sintaksin 1A genleri ile ilişkisi ve bu genlerin nöropsikolojik fonksiyonlar üzerine etkisi (Uzmanlık tezi). Denizli, Pamukkale Üniversitesi.
Kalueff A, Fox M, Gallagher P, Murphy D (2007) Hypolocomotion, anxiety and serotonin syndrome‐like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav, 6:389-400.
Karakaş Ü (2012) MikroRNA (miRNA) oluşum yolağında yer alan gen polimorfizmlerinin dikkat eksikliği hiperaktivite bozukluğu riski üzerine olası etkilerinin araştırılması (Uzmanlık tezi). Mersin, Mersin Üniversitesi.
Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N et al. (2005) Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Mol Psychiatry, 10:939–943.
Kim C-H, Hahn MK, Joung Y, Anderson SL, Steele AH, Mazei-Robinson MS et al. (2006) A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder. Proc Natl Acad Sci U S A, 103:19164-19169.
Kim CH, Waldman ID, Blakely RD, Kim KS (2008). Functional gene variation in the human norepinephrine transporter. Ann N Y Acad Sci, 1129:256-260.
Kim J, Biederman J, Arbeitman L, Fagerness J, Doyle A, Petty C, Perlis R et al. (2007) Investigation of variation in SNAP‐25 and ADHD and relationship to comorbid major depressive disorder. Am J Med Genet B Neuropsychiatr Genet, 144:781-790.
Kostrzewa RM, Kostrzewa JP, Brown RW, Nowak P, Brus R (2008) Dopamine receptor supersensitivity: development, mechanisms, presentation, and clinical applicability. Neurotox Res, 14:121-128.
Lahey BB, Piacentini JC, McBurnett K, Stone P, Hartdaghn S, Hynd G (1988) Psychopathology in the parents of children with conduct disorder and hyperactivity. J Am Acad Child Adolesc Psychiatry, 27:163-170.
Langley K, Marshall L, van den Bree M, Thomas H, Owen M, O’Donovan M et al.(2004). Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. Am J Psychiatry, 161:133-138.
Lasky‐Su J, Anney RJ, Neale BM, Franke B, Zhou K, Maller JB (2008) Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet, 147:1355-1358.
Lasky‐Su J, Neale BM, Franke B, Anney RJ, Zhou K, Maller JB (2008) 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, 147:1345-1354.
Lee J, Laurin N, Crosbie J, Ickowicz A, Pathare T, Malone M (2008) Association study of the nicotinic acetylcholine receptor α4 subunit gene, CHRNA4, in attention‐deficit hyperactivity disorder. Genes Brain Behav, 7:53-60.
Leo D, Gainetdinov RR (2013). Transgenic mouse models for ADHD. Cell Tissue Res, 354:259-271 . Lesch K-P, Timmesfeld N, Renner TJ, Halperin R, Röser C, Nguyen TT et al.(2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm (Vienna), 115:1573-1585.
Maglott D, Feldblyum T, Durkin A, Nierman W (1996) Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). Mamm Genome, 7:400-401.
Maher BS, Marazita ML, Ferrell RE, Vanyukov MM (2002) Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet, 12:207-215.
Maisonpierre PC, Le Beau MM, Espinosa R , Ip NY, Belluscio L, de la Monte SM et al. (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3:gene structures, distributions, and chromosomal localizations. Genomics, 10:558–568.
Manolio TA, Rodriguez LL, Brooks L, Abecasis G, Ballinger D, Daly M et al.(2007) New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nature Genet, 39:1045-1051.
Manor I, Eisenberg J, Tyano S, Sever Y, Cohen H, Ebstein RP et al.(2001) Family‐based association study of the serotonin transporter promoter region polymorphism (5‐HTTLPR) in attention deficit hyperactivity disorder. Am J Med Genet, 105:91-95.
Mattson MP (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci, 1144:97–112.
Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C et al.(2002) Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry, 159:1896-1901.
Mill J, Caspi A, Williams BS, Craig I, Taylor A, Polo-Tomas M et al.(2006) Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention-deficit/hyperactivity disorder: evidence from 2 birth cohorts. Arch Gen Psychiatry, 63:462-469.
Morrison JR, Stewart MA (1974) Bilateral inheritance as evidence for polygenicity in the hyperactive child syndrome. J Nerv Ment Dis,158:226-228.
Nadder TS, Silberg JL, Eaves LJ, Maes HH, Meyer JM (1998). Genetic effects on ADHD symptomatology in 7-to 13-year-old twins: results from a telephone survey. Behav Genet, 28:83-99.
Neale BM, Lasky‐Su J, Anney R, Franke B, Zhou K, Maller JB et al. (2008) Genome-wide association scan of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet, 147:1337-1344.
Nyholt DR (2012) Principles of linkage analysis. In Statistical Genetics (Eds B Neale, M Ferreira, S Medland, D Posthuma):113-134. New York, NY, Taylor Francis.
O’Neill MF, Heron-Maxwell CL, Shaw G (1999) 5-HT 2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D 1 agonist C-APB. Pharmacol Biochemist Behav, 63:237-243.
Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C et al. (2003) A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet, 72:1268-1279.
Omenn GS (1973) Genetic issues in the syndrome of minimal brain dysfunction. Semin Psychiatry, 5:5-17.
Öner Ö, Akın A, Herken H, Erdal ME, Çiftçi K, Ay ME et al. (2011) Association among SNAP-25 Gene Dde I and Mnl I polymorphisms and hemodynamic changes during methylphenidate use: a functional near-ınfrared spectroscopy study. J Atten Disord, 15:628-637.
Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter. Nature, 350:350-354.
Park MH, Kim JW, Yang YH, Hong SB, Park S, Kang H et al. (2012) Regional brain perfusion before and after treatment with methylphenidate may be associated with the G1287A polymorphism of the norepinephrine transporter gene in children with attention-deficit/hyperactivity disorder.Neurosci Lett, 14:159–163.
Pazvantoğlu O, Güneş S, Karabekiroğlu K, Yeğin Z, Sarısoy G, Korkmaz IZ et al. (2012) The relationship between ADHD and norepinephrine transporter gene polymorphism in a genetically loaded population. Klinik Psikofarmakol Bülteni, 22(Suppl 1):S145.
Porzgen P, Bonisch H, Bruss M (1995) Molecular cloning and organization of the coding region of the human norepinephrine transporter gene. Biochem Biophys Res Comm, 215:1145-1150.
Reeves JC, Werry JS, Elkind GS, Zametkin A (1987) Attention deficit, conduct, oppositional, and anxiety disorders in children: II. clinical characteristics. J Am Acad Child Adolesc Psychiatry, 26:144-155.
Retz W, Rösler M, Kissling C, Wiemann S, Hünnerkopf R, Coogan A et al. (2008) Norepinephrine transporter and catecholamine-O-methyltransferase gene variants and attention-deficit/hyperactivity disorder symptoms in adults. J Neural Transm (Vienna), 115:323-329.
Rhee SH, Waldman ID, Hay DA, Levy F (1999) Sex differences in genetic and environmental influences on DSM–III–R attention-deficit/hyperactivity disorder. J Abnorm Psychol, 108:24-41.
Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH (2002) Further evidence for the association between attention‐deficit/hyperactivity disorder and the dopamine‐β‐hydroxylase gene. Am J Med Genet, 114:154-158.
Romanos M, Freitag C, Jacob C, Craig D, Dempfle A, Nguyen T et al. (2008) Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13. 1 and 14q12. Mol Psychiatry, 13:522-530.
Russell VA (2011) Overview of animal models of attention deficit hyperactivity disorder (ADHD). Curr Protoc Neurosci, 9:Unit9.35.
Russell VA, Sagvolden T, Johansen EB (2005) Animal models of attention-deficit hyperactivity disorder. Behav Brain Funct, 1:9.
Safer DJ (1973) A familial factor in minimal brain dysfunction. Behav Genet, 3:175-186.
Schmitz M, Denardin D, Silva TL, Pianca T, Roman T, Hutz MH et al. (2006) Association between alpha-2a-adrenergic receptor gene and ADHD inattentive type. Biol Psychiatry, 60:1028-1033.
Sevinc E, Erdal ME, Sengul C, Cakaloz B, Ergundu TG, Herken H (2010) Association of adult attention deficit hyperactivity disorder with dopamine transporter gene, dopamine D3 receptor, and dopamine D4 receptor gene polymorphisms. Klinik Psikofarmakol Bülteni, 20:196-203.
Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D et al. (2007) Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry, 64:921-931.
Sherman DK, Iacono WG, McGUE MK (1997) Attention-deficit hyperactivity disorder dimensions: a twin study of inattention and impulsivity-hyperactivity. J Am Acad Child Adolesc Psychiatry. 36:745-753.
Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ et al. (2002) Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. Am J Hum Genet, 71:959-963.
Sontag TA, Tucha O, Walitza S, Lange KW (2010). Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review. Attent Defic Hyperact Disord, 2:1-20.
Sonuga‐Barke EJ, Lasky‐Su J, Neale BM, Oades R, Chen W, Franke B et al. (2008). Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan. Am J Med Genet B Neuropsychiatr Genet, 147:1359-1368.
Sparkes RS, Lan N, Klisak I, Mohandas T, Diep A, Kojis T et al. (1991) Assignment of a serotonin 5HT-2 receptor gene (HTR2) to human chromosome 13q14–q21 and mouse chromosome 14. Genomics, 9:461-465.
Spencer T, Biederman J (2001) Non-stimulant treatment for attention-deficit/hyperactivity disorder. J Atten Disord, 6:S109-119.
Sprich S, Biederman J, Crawford MH, Mundy E, Faraone SV (2000) Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry, 39:1432-1437.
Stahl S (2012) Stahl’ın Temel Psikofarmakolojisi (Çev. Ed. İT Uzbay). İstanbul, İstanbul Tıp Kitabevi.
Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR et al.(1995). A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genet, 11:201-203.
Stevenson J (1992) Evidence for a genetic etiology in hyperactivity in children. Behav Genet, 22:337-344.
Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N et al. (2007) Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev, 17:39-59.
Şimşek Ş, Gökçen C, Fettahoğlu Ç (2012) Dikkat eksikliği hiperaktivite bozukluğu (DEHB) olan çocukların ebeveynlerinde DEHB ve diğer psikiyatrik belirtiler. Dusunen Adam, 25, 230-237.
Tahir E, Curran S, Yazgan Y, Ozbay F, Cirakoglu B, Asherson PJ (2000a) No association between low‐and high‐activity catecholamine‐methyl‐transferase (COMT) and attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Am J Med Genet, 96:285-288.
Tahir E, Yazgan Y, Cirakoglu B, Ozbay F, Waldman I, Asherson PJ (2000b) Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Mol Psychiatry, 5:396-404. Taner HA, Sener S, Ergün SG, Ergün MA, Güney E (2014) Analysis of GNAL polymorphisms in attention deficit hyperactivity disorder. Int J Hum Genet, 14:149-153.
Thapar A, Holmes J, Poulton K, Harrington R (1999) Genetic basis of attention deficit and hyperactivity. Br J Psychiatry, 174:105-111.
Tüfekçi A (2009) Çocuk ve ergende dikkat eksikliği hiperaktivite bozukluğu’ndaki metilentetrahidrofolat redüktaz geni polimorfizminin moleküler genetik yöntemle araştırılması (Uzmanlık tezi). Bursa, Uludağ Üniversitesi.
Ünal GA, Kenar Aİ, Herken H, Tepeli E, Kıroğlu Y (2012) The relationship between SNAP-25 gene polymorphism and response to the treatment of methylphenidate hcl in adhd. Klinik Psikofarmakol Bulteni, 22(Suppl1):S157.
Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW et al. (1992) Human dopamine transporter gene (DAT1) maps to chromosome 5p15. 3 and displays a VNTR. Genomics, 14:1104-1106.
Varolgüneş D (1999) Dikkat eksikliği hiperaktivite bozukluğu (DEHB) olan çocuk ve ergenlerin anne ve babalarında psikiyatrik özellikler ve DEHB'un araştırılması (Uzmanlık tezi). İzmir, Ege Üniversitesi.
Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA (2006) ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biol Psychiatry, 59:1065-1070.
Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF (2005) Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry, 57:1336-1346.
Wilson MC (2000) Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder. Neuroscience Biobehav Rev, 24:51-57.
Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW et al. (2000) Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nature Neurosci, 3:465-471.
Xu X, Knight J, Brookes K, Mill J, Sham P, Craig I et al. (2005) DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder: no evidence for association. Am J Med Genet B: Neuropsychiatr Genet, 134:115-118.
Xu X, Hawi Z, Brookes KJ, Anney R, Bellgrove M, Franke B et al. (2008) Replication of a rare protective allele in the noradrenaline transporter gene and ADHD. Am J Med Genet B Neuropsychiatr Genet, 147:1564-1567.
Yang B, Chan RC, Jing J, Li T, Sham P, Chen RY (2007) A meta‐analysis of association studies 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, 144:541-550.
Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T et al. (2001) A quantitative-trait analysis of human plasma–dopamine β-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet, 68:515-522.
Zhang HB, Wang YF, Li J, Wang B, Yang L (2005) [Association between dopamine beta hydroxylase gene and attention deficit hyperactivity disorder complicated with disruptive behavior disorder]. Zhonghua Er Ke Za Zhi, 43:26-30.
Zhou K, Dempfle A, Arcos‐Burgos M, Bakker SC, Banaschewski T, Biederman J et al. (2008) Meta‐analysis of genome‐wide linkage scans of attention deficit hyperactivity disorder. Am J Med Genet B: Neuropsychiatr Genet,147:1392-1398.
Zoroğlu SS, Erdal ME, Alaşehirli B, Erdal N, Sivasli E, Tutkun H et al. (2002) Significance of serotonin transporter gene 5-HTTLPR and variable number of tandem repeat polymorphism in attention deficit hyperactivity disorder. Neuropsychobiology, 45:176-181.
Zoroglu SS, Erdal ME, Erdal N, Ozen SIR, Alasehirli B, Sivasli E (2003) 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, 47:17-20