Study Report

Basic Info
Reference |
Brookes KJ, 2008(a)18668530
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Citation |
Brookes K. J., Xu X., Anney R., Franke B., Zhou K., Chen W., Banaschewski T., Buitelaar J., Ebstein R., Eisenberg J., Gill M., Miranda A., Oades R. D., Roeyers H., Rothenberger A., Sergeant J., Sonuga-Barke E., Steinhausen H. C., Taylor E., Faraone S. V. and Asherson P. (2008) "Association of ADHD with genetic variants in the 5'-region of the dopamine transporter gene: evidence for allelic heterogeneity." Am J Med Genet B Neuropsychiatr Genet, 147B(8): 1519-23.
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Study Design |
family-based |
Study Type |
Candidate-gene association study |
Sample Size |
988 affected probands and 150 of their affected siblings |
Predominant Ethnicity |
Caucasian |
Population |
Belgium, Germany, the Netherlands, Ireland, Israel, Spain, Switzerland, United Kingdom |
Age Group |
Children/Adolescents
:
5-17 years
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Detail Info
Summary |
They previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study they replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD. |
Total Sample |
the final combined ST1 and ST2 dataset used in this study consisted of 1,147 individuals with DSM-IV combined subtype ADHD from 988 affected probands and 150 of their affected siblings. |
Replication Size |
376 probands plus 59 affected siblings |
Sample Collection |
European Caucasian |
Diagnosis Description |
The diagnosis of ADHD was made following a parent interview with the Parental Account of Child Symptoms interview that asks about ADHD symptoms in various settings. The diagnosis of ADHD was made if sufficient items were identified to fulfill DSM-IV criteria, and both impairment and pervasiveness were present. More details could be found in the original study. |
Technique |
Genotyping of the 3' UTR and intron 8 VNTRs were previously carried out in the ST2 (replication) sample and the results reported elsewhere [Asherson et al., 2007]. The SNP markers were genotyped using the ABI SNPlex and ABI TaqMan genotyping protocols. |
Analysis Method |
The transmission disequilibrium test was performed for probands with the combined subtype of ADHD using the UNPHASED program. Nominal evidence for association was determined by P-values less than 0.05 and adjusted significance estimated by permutation tests. In addition we utilized the WHAP program to conduct conditional analyses that test the contribution of genetic variants to haplotype associations. |
Result Description |
These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. |

SNPs reported by this study (count: 4)
SNP |
Allele Change |
Risk Allele |
Statistical Values |
Author Comments |
Result of Statistical Analysis |
rs11564750 |
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G |
ST1 TDT P-value=0.03, OR=1.35; ST2 TDT P-value=0.004, OR=1.76; ST1&ST2 TDT P-value=0.0006, OR=1.47 |
showed nominal significance (P<0.01) and surpassed the Bonfe......
showed nominal significance (P<0.01) and surpassed the Bonferroni correction for the four markers tested in ST2; nominally significant associations in the combined analysis of ST1 and ST2
More...
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Significant
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rs40184 |
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C |
ST1 TDT P-value=0.005, OR=1.26; ST2 TDT P-value=0.31, OR=1.13; ST1&ST2 TDT P-value=0.005, OR=1.2 |
not significantly associated in ST2; nominally significant a......
not significantly associated in ST2; nominally significant associations in the combined analysis of ST1 and ST2
More...
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Significant
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rs2550946 |
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G |
ST1 TDT P-value=0.006, OR=1.24; ST2 TDT P-value=0.45, OR=1.1; ST1&ST2 TDT P-value=0.01, OR=1.19 |
not significantly associated in ST2; nominally significant a......
not significantly associated in ST2; nominally significant associations in the combined analysis of ST1 and ST2
More...
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Significant
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rs3776513 |
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G |
ST1 TDT P-value=0.05, OR=1.24; ST2 TDT P-value=0.01, OR=1.57; ST1&ST2 TDT P-value=0.009, OR=1.28 |
showed nominal significance (P<0.01) and surpassed the Bonfe......
showed nominal significance (P<0.01) and surpassed the Bonferroni correction for the four markers tested in ST2; nominally significant associations in the combined analysis of ST1 and ST2
More...
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Significant
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Genes reported by this study (count: 1)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
SLC6A3 |
two marker haplotype P-value=0.00002; four marker haplotype ......
two marker haplotype P-value=0.00002; four marker haplotype GGGC P-value=1.8E-6; the most significant finding occurred between rs2550946 and rs40184; a four-marker haplotype displays significant over transmission to ADHD probands
More...
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Significant
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