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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	Franke B, 201019890261
Citation	Franke B., Vasquez A. A., Johansson S., Hoogman M., Romanos J., Boreatti-Hummer A., Heine M., Jacob C. P., Lesch K. P., Casas M., Ribases M., Bosch R., Sanchez-Mora C., Gomez-Barros N., Fernandez-Castillo N., Bayes M., Halmoy A., Halleland H., Landaas E. T., Fasmer O. B., Knappskog P. M., Heister A. J., Kiemeney L. A., Kooij J. J., Boonstra A. M., Kan C. C., Asherson P., Faraone S. V., Buitelaar J. K., Haavik J., Cormand B., Ramos-Quiroga J. A. and Reif A. (2010) "Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD." Neuropsychopharmacology, 35(3): 656-64.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	1404 persistent ADHD patients and 1680 controls in the original analysis, and 1440 patients with adult ADHD and 1769 controls in the meta-analysis
Predominant Ethnicity	Caucasian
Population	Germany, Norway, Spain, the Netherlands
Age Group	Adults : adults

Detail Info

Summary	In this study, they carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3'-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3'-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.
Total Sample	Within the IMpACT group, 1404 persistent ADHD patients and 1680 controls, in which both VNTRs had been genotyped, were considered for inclusion in the study. The meta-analysis included data from another published report on the DAT1 VNTR haplotype in adults (Bruggemann et al, 2007), which increased the total number of genotypes included further to 1440 patients with adult ADHD and 1769 controls.
Sample Collection	All subjects were of Caucasoid origin
Diagnosis Description	Consensus eligibility criteria for this study across all study sites were a diagnosis of ADHD according to the diagnostic criteria of DSM-IV, onset before the age of 7 years by retrospective diagnosis (which was confirmed by a family member, wherever possible), life-long persistence and current diagnosis. Please refer to the original article for more details.
Technique	Genotyping of the 40 bp VNTR located in the 3'-UTR of DAT1 had been carried out earlier at the different IMpACT sites. Procedures and/or references can be found in Supplementary File in the original article.
Analysis Method	Haplotypes were estimated using the haplo.em function implemented in the haplo.stats package. A combined analysis was carried out including the samples of IMpACT only. A trend test was used to evaluate the ADHD risk conferred by carrying the 9-6 haplotype using basic X² and logistic regression tests. To combine the individual study results, they conducted meta-analyses using RevMan (version 5.0.2) (The Cochrane Collaboration, 2008). Please refer to the original article for more details.
Result Description	Both the 9-6 haplotype (3'-UTR VNTR/Intron 8 VNTR) and the 9/9 genotype of the 3'-UTR VNTR showed association with the disorder in adults using two different analysis methods, ie, a combined analysis and a meta-analysis design. The intron 8 VNTR by itself did not seem to increase persistent ADHD risk.

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A3 3'-UTR VNTR			9/9 genotype P-value=0.005, OR=1.5, X² (1df)=8.15...... 9/9 genotype P-value=0.005, OR=1.5, X² (1df)=8.15, meta-analysis P-value=0.03, OR=1.34; 10/10 genotype meta-analysis P-value=0.29, OR=0.93 More...	the 9/9 genotype of the 3'-UTR VNTR showed association with the disorder in adults in the combined and meta-analysis	Significant
SLC6A3 intron8 VNTR			no P-value no P-value	no significant association	Non-significant

Genes reported by this study (count: 1)