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	Sanchez-Mora C, 201121595008
Citation	Sanchez-Mora C., Ribases M., Casas M., Bayes M., Bosch R., Fernandez-Castillo N., Brunso L., Jacobsen K. K., Landaas E. T., Lundervold A. J., Gross-Lesch S., Kreiker S., Jacob C. P., Lesch K. P., Buitelaar J. K., Hoogman M., Kiemeney L. A., Kooij J. J., Mick E., Asherson P., Faraone S. V., Franke B., Reif A., Johansson S., Haavik J., Ramos-Quiroga J. A. and Cormand B. (2011) "Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: a meta-analysis in four European populations." Am J Med Genet B Neuropsychiatr Genet, 156(5): 600-12.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	1608 adult ADHD patients and 2352 controls
Predominant Ethnicity	Caucasian
Population	Spain, Germany, Norway, the Netherlands
Gender	1125 (47.8%) female and 1227 (52.2%) male controls, 720 (44.8%) female and 888 (55.2%) male cases
Age Group	Adults : Germany: mean age=33.91, SD=10.12 of cases; mean age=30.73, SD=9.8 of controls. Netherlands: mean age=41.23, SD=11.35 of cases; mean age=63.46, SD=18.07 of controls. Norway: mean age=33.9, SD=11.6 of cases; mean age=27.4, SD=7.16 of controls. Spain: mean age=36.02, SD=16.83 of cases; mean age=45.26, SD=14.79 of controls

Detail Info

Summary	They analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiplemarker meta-analysis showed a nominal association of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since they previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3 'UTR VNTR-intron 8 VNTR) in the same dataset, they further tested for gene-gene interaction between DRD4 and SLC6A3. However, they detected no epistatic effects but their results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.
Total Sample	In total, 1608 adult ADHD patients and 2352 controls of Caucasian origin from four European countries (Spain, Germany, Norway, and the Netherlands) were recruited at four sites of IMpACT.
Sample Collection	The sample was recruited at four sites of IMpACT (Spain, Germany, Norway, and the Netherlands).
Diagnosis Description	Consensus eligibility criteria for the current study across all sites were a diagnosis of ADHD according to the diagnostic criteria of Diagnostic and Statistical Manual for Mental Disorders-IV (DSM-IV), onset before the age of 7 years via retrospective diagnosis (which was confirmed by a family member, wherever possible), lifelong persistence, and current diagnosis.
Technique	Genomic DNA was isolated either from saliva using the Oragene DNA Self-Collection Kit (DNA Genotek Inc., Ottawa, Ontario, Canada) or from peripheral blood lymphocytes by the salting-out procedure [Miller et al., 1988]. Genotyping was carried out using standard PCR methods.
Analysis Method	They first performed a single-and multiple-marker analysis on the samples from the four IMpACT sites, separately, and then analyzed the pooled sample using a meta-analytical approach. Genotype and allele frequencies were compared between cases and controls fromeach separate IMpACT site using a chi-squared test with the SNPassoc R package and the statistical package SPSS 15.0, respectively. Haplotype frequencies were estimated using the PHASE software [Stephens et al., 2001]. They conducted a meta-analysis using the Meta R package (www.cran.rproject. org/web/packages/meta/index.html). A logistic regression analysis was used to evaluate the independent and interactive effects of the DRD4 and SLC6A3 loci.
Result Description	Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiplemarker meta-analysis showed anominal association (P=0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. They detected no epistatic effects of gene-gene interaction between DRD4 and SLC6A3 but the results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
DRD4 promoter duplication 120bp			chi-square test P-value>0.05 for allele and genotype frequen...... chi-square test P-value>0.05 for allele and genotype frequencies from each separate site; P-value=0.009, OR=1.69 between L allele and ADHD in males from Norway; P-value=0.04, OR=1.40; P-value=0.04, OR=2.63 in combined subtype in Norway and in Spain respectively; meta-analysis: P-value=0.30, OR=0.81 in dominant model (LS+LL vs. SS), P-value=0.52, OR=1.05 in recessive model (LL vs. LS+SS), P-value=0.80, OR=0.98 in overdominant model (LS vs. LL+SS) More...	no significant association was detected for genotype and allele frequencies between cases and controls from each separate site; a nominal association between the L allele of the dup120bp polymorphism and ADHD in males from Norway; nominal association was also observed in two samples from Norway and Spain in the combined clinical subtype; no significant association was found for dup120bp in the full ADHD sample in the meta-analysis	Significant
DRD4 exon3 VNTR			chi-square test P-value>0.05 for allele and genotype frequen...... chi-square test P-value>0.05 for allele and genotype frequencies from each separate site; meta-analysis: P-value=0.78, OR=0.97 for 4R4R genotype versus others; P-value=0.52, OR=1.12 for 7R7R genotypes versus others; P-value=0.53, OR=0.87 for 4R7R genotypes versus others More...	no significant association between the 48bp VNTR and ADHD was identified in any of the European samples when studied separately; no association between the VNTR polymorphism and adult ADHD was seen in the full ADHD sample in the meta-analysis	Non-significant

Genes reported by this study (count: 2)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
DRD4	chi-square test P-value>0.05 for haplotype frequencies, show...... chi-square test P-value>0.05 for haplotype frequencies, showed no association in any of the four separate cohorts; meta-analysis: P-value=0.01, OR=0.78 showed an under representation of the S-4R allelic combination in the ADHD sample; P-value=0.04, OR=0.73 in females; S-4R P-value=0.01, OR=0.75; L-4R P-value=0.02, OR=1.29, showed an increased frequency of carriers of the L-4R risk haplotype in addition to an under-representation of the S-4R allelic combination in this clinical dataset. P-value=3.04e-05, OR=1.66; P-value=2.66e-05, OR=1.74 of DRD4 L-4R and SLC6A3 9R-6R increased the risk for ADHD in both the ADHD sample as a whole and in the combined clinical subtype respectively which suggested additive effects of the DRD4 risk haplotype and the SLC6A3 gene More...	Significant
SLC6A3	P-value=3.04e-05, OR=1.66; P-value=2.66e-05, OR=1.74 of DRD4...... P-value=3.04e-05, OR=1.66; P-value=2.66e-05, OR=1.74 of DRD4 L-4R and SLC6A3 9R-6R increased the risk for ADHD in both the ADHD sample as a whole and in the combined clinical subtype respectively which suggested additive effects of the DRD4 risk haplotype and the SLC6A3 gene More...	Significant