ADHDgene Database

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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Study Report

Basic Info

Reference	Kereszturi E, 200717171658
Citation	Kereszturi E., Kiraly O., Csapo Z., Tarnok Z., Gadoros J., Sasvari-Szekely M. and Nemoda Z. (2007) "Association between the 120-bp duplication of the dopamine D4 receptor gene and attention deficit hyperactivity disorder: genetic and molecular analyses." Am J Med Genet B Neuropsychiatr Genet, 144B(2): 231-6.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	173 cases and 284 controls
Predominant Ethnicity	Caucasian
Population	Hungary
Gender	87.3% male and 12.7% female
Age Group	Children/Adolescents : mean age 9.14 years (SD=2.6)

Detail Info

Summary	Here we describe the haplotype analysis of the 120 base pair duplication (120-bp dup) and three SNPs (-616C/G, -615A/G, -521C/T) in the 50 region of the DRD4 gene among children with ADHD. We observed a trend in the four-locus haplotype distribution between ADHD probands (N=173) and controls (N=284). The homozygote genotype of the 1-repeat form of the 120-bp dup (1-1) had a significantly higher frequency among ADHD children than in controls. In addition, a novel, 4-repeat allele was identified among ADHD patients. This particular allele has been cloned to the luciferase expression vector and its transcriptional activity has been compared to the 1- and 2-repeat allele. The number of repeats of the 120-bp dup was found to have an effect on transcriptional activity in both neuroblastoma and retinoblastoma cell lines in a dose-dependent manner (1-repeat>2-repeat>4-repeat). These re- sults suggest that the 1-repeat form of the 120-bp dup might be a risk factor of ADHD, especially in the homozygous form and/or in the context of certain haplotypes.
Total Sample	173 ADHD patients (combined subtype: 72%; inattentive subtype: 13%; hyperactive-impulsive subtype: 15%) and 284 controls were included. According to the MINI-Kid, the frequencies of comorbidities were the following: learning disorder: 30.6%; conduct disorder: 28.9%; anxiety disorder: 13.3%; Tourette syndrome: 12.1%.
Sample Collection	ADHD patients were from the Vadaskert Child and Adolescent Psychiatric Clinic. The sex-matched control group was selected from the previously described healthy Hungarian population [Szantai et al., 2005]. Both the clinical and the control samples were ethnically homogenous, Caucasian and consisted of unrelated individuals.
Diagnosis Description	Diagnosis of ADHD was based on DSM-IV criteria [USAn Psychiatric Association, 1994], and was confirmed by the Child Behaviour Checklist [Achenbach, 1991], the Conners Rating Scale [Conners et al., 1998], and the ADHD Rating Scale [DuPaul, 1998]. The diagnostic procedure was conducted by two independent psychiatrists and inter-rater reliability (kappas) reached 0.95 for all diagnoses. Children with IQ<80 were excluded, as well as those who had severe medical or neurological conditions or pervasive psychiatric disorder. IQ was estimated from the Raven progressive matrices test [Raven, 1965]. Comorbid conditions were assessed by a semi-structured interview, the Hungarian child version of the Mini-International Neuropsy-chiatric Interview[MINI-Kid;Balazs et al., 2004]. The study was approved by the Local Ethical Committee (TUnited KingdomEB).
Technique	Non-invasive DNA sampling was applied as described else where [Boor et al., 2002]. Genotyping of the -616C/G SNP was performed using methods not affected by the -615A/G SNP. The -521C/T SNP was genotyped with methods insensitive to the -603 Tdel polymorphism. Direct molecular haplotyping of the four promoter polymorphisms was performed as described previously [Szantai et al., 2005]. For more details about methods of plasmid constructs, cell culture and transient transfections, please refer to the original publication.
Analysis Method	SPSS 10.0 for Windows was used in the association analyses. The association analyses were also carried out with estimated haplotypes using the EH program elaborated by Ott [2003]. Statistical analysis for transcriptional data was performed with one-way ANOVA followed by the TUnited Kingdomey-Kramer Multiple Comparison Test (GraphPad InStat).
Result Description	Single-locus analysis was performed to four polymorphisms in the 5' regulatory region of the DRD4 gene. The 120-bp dup, -616C/G SNP, -521C/T SNP, and the newly identified -615A/G SNP were assessed. No linkage disequilibrium was detected between the 120-bp dup and any of the SNPs. No significant deviations from Hardy-Weinberg equilibrium were detected for any of the polymorphisms either in the case or in the sex-matched control population. There was no significant difference between the ADHD and control groups in the allele frequency of the investigated SNPs. However, a significant difference was detected in the allelic distribution of the 120-bp dup. Four-locus haplotype frequencies were analyzed in cases and controls using direct haplotypingmethods. There was a tendency for an unequal distribution. An accumulation of the 1-C-A-T haplotype (1-repeat allele of the 120-bp dup~-616C~-615A~-521T) was detected among ADHD children. The estimated haplotype frequencies of the control and the ADHD samples did not differ significantly from the original frequencies detected with direct haplotype methods.

Other variant reported by this study (count: 4)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
DRD4 promoter -521C/T	C/T			No association was found between ADHD and this SNP	Non-significant
DRD4 promoter -615A/G	A/G			No association was found between ADHD and this SNP	Non-significant
DRD4 promoter duplication 120bp			P-value=0.047 (df=1) for allelic distribution; P-value=0.019...... P-value=0.047 (df=1) for allelic distribution; P-value=0.019 (OR=2.71) for homozygote genotype analysis More...	No association was found between ADHD and this polymorphism, howerer, an overrepresentation of the 1-repeat form of the 120-bp dup was observed in the clinical group.	Significant
DRD4 promoter -616C/G	C/G			No association was found between ADHD and this SNP	Non-significant

Genes reported by this study (count: 1)