Study Report

Basic Info
Reference |
Doyle C, 200919576958
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Citation |
Doyle C., Brookes K., Simpson J., Park J., Scott S., Coghill D. R., Hawi Z., Kirley A., Gill M. and Kent L. (2009) "Replication of an association of a promoter polymorphism of the dopamine transporter gene and Attention Deficit Hyperactivity Disorder." Neurosci Lett, 462(2): 179-81.
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Study Design |
family-based |
Study Type |
Candidate-gene association study |
Sample Size |
450 probands and their parents |
Predominant Ethnicity |
Caucasian |
Population |
United Kingdom, Ireland |
Gender |
90.1% male |
Age Group |
Children/Adolescents
:
aged 4-15
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Detail Info
Summary |
The current study aims to replicate association findings from the International Multicentre ADHD Genetics (IMAGE) project in one of the most studied genes related to ADHD, the dopamine transporter (DAT1) gene. In a family-based sample of 450 ADHD probands, three Single Nucleotide Polymorphism (SNP) markers have been genotyped using TaqMan assays. Transmission Disequilibrium Test analysis demonstrates that one of three SNP markers (rs11564750) in the 5 promoter region of the gene is significantly associated with ADHD (P-value= 0.02). This provides further evidence that in addition to the well-known and investigated 3 UTR polymorphism associated with ADHD, there is potentially a further association signal emanating from the 5 promoter region of the gene. Further replication and functional studies are now required to fully understand the consequence of polymorphisms present at both the 5 and 3 ends of the DAT1 gene and their role in ADHD pathophysiology. |
Total Sample |
450 ADHD probands (inclusive of 12 affected siblings) and their parents from United Kingdom (N=183) and Ireland (N=267) were recruited in this study. Of these N=42 (9.3%) had the inattentive subtype, and N=38 (8.4%) had the hyperactive impulsive subtype, the rest had the combined subtype (82.3%). Two hundred and eleven children (46.9%) had comorbid oppositional defiant disorder and 69 children (15.3%) fulfilled criteria for comorbid conduct disorder. Frequencies of subtype and comorbiditywere similar across the two recruitment centres. |
Sample Collection |
All probandswere white and born in the United Kingdom or Ireland. |
Diagnosis Description |
Parents were interviewed by trained psychiatrists or psychologistsemploying the Child and Adolescent Psychiatric Assessment (CAPA). Consistent interview procedures were employed across the two centres with researchers from each centre receiving a common training in the use of the CAPA. In addition teacher ratings were obtained for children by the Conners Teacher Rating Scale (CTRS). This was to confirm that symptoms met the criterion of pervasiveness. Established cut-off points for possible and likely ADHD caseness on the CTRS were adhered to, i.e. a T score above 55 was required. All probands fulfilled DSM-IV diagnostic criteria for Attention Deficit Hyperactivity Disorder (ADHD). Children with an IQ below 70, autistic spectrum disorder or significant medical conditions such as epilepsy were excluded. |
Technique |
High molecular weight genomic DNA was extracted from either whole blood (Wizard Genomic DNA Purification A1620, Promega, WI) or cheek swab according to routine procedures. Genotyping of the three SNP markerswas carried out by TaqMan Genotyping Assays from Applied Biosciences (Applied Biosciences, Foster City, CA). Assays were conducted following the Applied Biosciences standard protocols and run on an Mx3005P (Stratagene, CA) with allele calls determined by MxPro Software version 4.0 (Stratagene, CA). Samples where allele calls were ambiguous were repeated. |
Analysis Method |
Transmission Disequilibrium Test (TDT) analysis of the sample was carried out using the UNPHASED software suite of programmes for the association analysis of multi-locus genotype data in families and unrelated subjects. In cases where affected siblings are present (N=12), the parental genotypes are recounted and treated as an independent trio for analysis. Evidence for association of the marker with ADHD was set at the 0.05 level of significance. Given that this study was testing a specific a priori hypothesis, aiming to replicate previous significant findings, results have not been corrected for multiple testing. |
Result Description |
The current study observed an association with one of the three SNP markers. The 5' promoter SNP marker rs11564750 displayed nominal statistical significance (P-value=0.02) with the G-allele over transmitted to ADHD probands (T:56 NT:34, OR:1.65). TDT analysis for both the other SNPs, although not reaching statistical significance demonstrated ORs greater than 1. For rs2550946, this finding is in the same direction as the previous IMAGE finding with the G-allele being over transmitted, but for rs41804, the opposite allele was over transmitted to that found in the IMAGE study. |

SNPs reported by this study (count: 3)
SNP |
Allele Change |
Risk Allele |
Statistical Values |
Author Comments |
Result of Statistical Analysis |
rs11564750 |
G:C |
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TDT P-value=0.02 with T:56 NT:34, OR:1.65 |
Displayed nominal statistical significance with the G-allele......
Displayed nominal statistical significance with the G-allele over transmitted to ADHD probands.
More...
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Significant
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rs2250946 |
G:A |
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TDT P-value=0.38 with T:130 NT:116, OR:1.12 |
No statistical significant association was found between thi......
No statistical significant association was found between this marker and ADHD.
More...
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Non-significant
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rs40184 |
T:C |
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TDT P-value=0.56 with T:124 NT:115, OR:1.08 |
No statistical significant association was found between thi......
No statistical significant association was found between this marker and ADHD.
More...
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Non-significant
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Genes reported by this study (count: 1)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
SLC6A3 |
Association signal was identified in the 5' region of this g......
Association signal was identified in the 5' region of this gene.
More...
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Significant
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