Abstract OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is one of the most common behavior disorders in childhood and adolescent. The etiology of ADHD is unknown. The aim of this study was to investigate the relationship between each of the 14 polymorphisms in the five candidate genes and ADHD, and between the combination of some polymorphisms in those genes and ADHD, in attempting to examine whether combinations of genotypes would confer a significant susceptibility to ADHD. METHODS: One hundred and thirty-nine children with ADHD and one hundred and nineteen normal children were enrolled. Eight single nucleotide polymorphisms (SNP) of three candidate genes were examined with PCR and RFLP techniques. 48 bp VNTR in DRD4 gene was examined with PCR, nondenaturing polyacrylamide gel electrophoresis and silver staining. Five microsatellites (MS) of three candidate genes were examined with genotyping. The relationship between the combinations of 12 polymorphisms and ADHD was examined with logistic regression analysis. RESULTS: 1.The frequency of 1065T/1065T genotype and the 1065T allele were significantly higher in ADHD children than that in normal controls (P<0.05). The frequency of -48G/-48G genotype of the A-48G polymorphism of DRD1 gene was significantly lower in ADHD children than that in normal controls (P<0.05). 2. A specific combination of three polymorphisms in the two genes showing an association with ADHD gave a prediction level of 77.5%.ConclusionsThe T1065G polymorphism in the SNAP-25 may be associated with ADHD. The 1065T/ 1065T genotype and the 1065T allele may be a risk factor for ADHD. The A-48G polymorphism of DRDI may be associated with ADHD. The-48G/-48G genotype may be a protective factor for ADHD. The specific combination of three sites of SNP in SNAP-25 gene and DRDI gene is found and shows an association with ADHD in 12 polymorphisms of the five candidate genes on glutamatergic/dopaminergic pathway. [Chin J Contemp Pediatr, 2009, 11 (8):617-622]
GAO Xue-Ping,SU Lin-Yan,ZHAO Ai-Ling et al. Association of 14 polymorphisms in the five candidate genes and attention deficit hyperactivity disorder[J]. 中国当代儿科杂志, 2009, 11(08): 617-622.
GAO Xue-Ping,SU Lin-Yan,ZHAO Ai-Ling et al. Association of 14 polymorphisms in the five candidate genes and attention deficit hyperactivity disorder[J]. CJCP, 2009, 11(08): 617-622.
[1]Albayrak O, Friedel S, Schimmelmann BG, Hinney A, Hebebrand J. Genetic aspects in attention-deficit/hyperactivity disorder[J]. J Neural Transm, 2008, 115(2):305-315.
[2]Thapar A, Langley K, Owen MJ, O′Donovan MC. Advances in genetic findings on attention deficit hyperactivity disorder[J]. Psychol Med, 2007, 37(12):1681-1692.
[4]Faraone SV. Genetics of adult attention-deficit/hyperactivity disorder[J]. Psychiatr Clin North Am, 2004, 27(2):303-321.
[5]Heiser P, Friedel S, Dempfle A, Konrad K, Smidt J, Grabarkiewicz J, et al. Molecular genetic aspects of attention-deficit/hyperactivity disorder[J]. Neurosci Biobehav Rev, 2004, 28(6):625-641.
[6]Kent L. Recent advances in the genetics of attention deficit hyperactivity disorder [J].Curr Psychiatry Rep, 2004, 6(2):143-148.
[7]Mill J, Xu X, Ronald A, Curran S, Price T, Knight J, et al. Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B[J]. Am J Med Genet B Neuropsychiatr Genet, 2005, 133B(1):68-73.
[8]Mill J, Curran S, Kent L, Gould A, Huckett L, Richard S, et al. Association study of a SNAP-25 microsatellite and attention deficit hyperactivity disorder [J]. Am J Med Genet, 2002, 114(3):269-271.
[9]Turic D, Langley K, Mills S, Stephens M, Lawson D, Govan C, et al. Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2 A gene polymorphism with ADHD[J]. Mol Psychiatry, 2004, 9(2):169-173.
[10]Misener VL, Luca P, Azeke O, Crosbie J, Waldman I, Tannock R, et al. Linkage of the dopamine receptor Dl gene to attention-deficit/hyperactivity disorder[J].Mol Psychiatry, 2004, 9(5):500-509.
[11]Mill J, Curran S, Richards S, Taylor E, Asherson P. Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD [J]. Am J Med Genet B Neuropsychiatr Genet, 2004, 125B(1):38-42.
[12]Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK, et al. Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11[J]. A m J Hum Genet, 2004, 75(4):661-668.
[13]Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, et al .Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2,5q33.3,11q22, and 17p11[J]. Am J Hum Genet, 2004, 75(6):998-1014.
[14]Russell VA. Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder—the spontaneously hypertensive rat [J]. Neurosci Biobehav Rev, 2003, 27(7):671-682.
[15]Russell VA, Sagvolden T, Johansen EB. Animal models of attention-deficit hyperactivity disorder[J]. Behav Brain Funct, 2005, 1:9.
[18]Mill J, Richards S, Knight J, Curran S, Taylor E, Asherson P, et al. Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD[J]. Mol Psychiatry, 2004, 9(8):801-810.
[19]Kim JW, Waldman ID, Faraone SV, Biederman J, Doyle AE, Purcell S, et al. Investigation of parent-of-origin effects in ADHD candidate genes[J]. Am J Med Genet B Neuropsychiatr Genet, 2007, 144B (6):776-780.
[20]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[J].Am J Med Genet B Neuropsychiatr Genet, 2005,134B(1):67-72.
[21]Kustanovich V, Ishii J, Crawford L, Yang M, McGough JJ, McCracken JT, et al. Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5[J]. Mol Psychiatry, 2004, 9(7):711-717.
[22]Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ, et al. Joint analysis of the DRD5 marker concludes association with attentiondeficit/ hyperactivity disorder confined to the predominantly inattentive and combined subtypes [J]. Am J Hum Genet, 2004, 74 (2):348-356.
[23]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[J]. Arch Gen Psychiatry, 2007, 64(8):921-931.
[25]Li D, Sham PC, Owen MJ, He L. Metaanalysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD)[J]. Hum Mol Genet, 2006, 15(14):2276-2284.
[26]Kim JW, Waldman ID, Faraone SV, Biederman J, Doyle AE, Purcell S, et al. Investigation of parent-of-origin effects in ADHD candidate genes[J]. Am J Med Genet B Neuropsychiatr Genet, 2007, 144B(6):776-80.
[27]Xu Q, Jia YB, Zhang BY, Zou K, Tao YB, Wang YP, et al. Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders [J]. Mol Psychiatry, 2004, 9(5):510-521.