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	Lowe N, 2004 (a)15389764
Citation	Lowe N., Kirley A., Mullins C., Fitzgerald M., Gill M. and Hawi Z. (2004) "Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616." Am J Med Genet B Neuropsychiatr Genet, 131B(1): 33-7.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	178 families
Predominant Ethnicity	Caucasian
Population	Ireland

Detail Info

Summary	In the absence of a firm link between the number of the VNTR repeats and the function of the gene, the current study sought to investigate several additional markers at the 5' end of the gene with potential influence on the expression of the DRD4. They observed a significant over transmission of SNP. In addition, an excess transmission of the A allele of the -521 SNP was observed, although it did not attain statistical significance. Linkage disequilibrium (LD) analysis demonstrated a weak level of D' between any of the tested markers implying that this may be a region of high recombination. It also raises the possibility that the new association with ADHD may be independent of the 7-repeat allele. Further analyses, preferably in samples demonstrating association with the VNTR, or in other ethnic groups, are required to confirm these observations.
Total Sample	178 families
Sample Collection	As part of ongoing studies on ADHD, 178 families with clinically diagnosed ADHD children were recruited from child clinics and ADHD support groups around Ireland.
Diagnosis Description	Clinical and diagnostic details can be found Kirley et al. [2004]
Technique	DNA was extracted from blood using a standard phenol/chloroform method or from buccal swabs as described in Gill et al. [1997]. Polymerase chain reaction (PCR) cycling was performed on a MJ Research DNA Engine. Amplification and genotyping of the 120 bp duplication and the VNTR polymorphisms can be found in Seaman et al. [1999] and Hawi et al. [2000], respectively. Genotyping of the -616, -521 and -376 SNPs was performed using the SNaPshot Method of single base extension [Norton et al., 2002]. This involves extending unlabelled primers by a single base using fluorescentl y tagged ddNTPs. Each of the four bases is labeled with a different colored fluorescent dye that can be detected when run on an ABI Genetic Analyzer (ABI PRISM 377 DNA Sequencer). The genotypes can then be assigned according to the product's size and the color. For more details, please refer to the original paper.
Analysis Method	The transmission disequilibrium test (TDT) was performed on each individual marker to test for association between each variant and ADHD. Extended TDT (ETDT) was used to analyze the multi-allelic VNTR marker. Linkage disequilibrium (expressed as D') between the studied markers was calculated from parental genotypes using the computer program GOLD. In addition, TRANSMIT, which tests for the association between a genetic marker and disease by examining the transmission of markers from parents to affected offspring, was used to analyze multi-marker haplotypes for the presence of associated with ADHD. The data presented in this manuscript has not been corrected for multiple testing.
Result Description	Increased transmission of the 7-repeat allele to ADHD cases was observed in the extended and refined sample, although it was not statistically significant. However, a significant association was observed between the C allele of the -616 SNP and ADHD. In addition, an insignificant excess of allele A of -521 was transmitted to affected offspring. No distortion in the transmission of the alleles at the marker -376 was observed. However, the frequency of the C allele was found to be only 5% in the Irish population. Significant evidence for LD was observed between the markers, -616 and -376, -521 and -376 and -376 and the VNTR. However, little or no evidence of LD was present between any of the other tested markers. Haplotype analysis between markers revealed a marginal significance between a haplotype constructed of the long allele of the 120 bp duplication and allele C of the -616 SNP and ADHD. Non-significant increase in the transmission of the -616 and the -521 haplotype and the -521 and VNTR haplotype to the ADHD individuals was observed.

Other variant reported by this study (count: 5)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
DRD4 exon3 VNTR		7 repeat	TDT P-value=0.198, OR=1.35, 95% CI=0.88-2.07 TDT P-value=0.198, OR=1.35, 95% CI=0.88-2.07	not statistically significant	Non-significant
DRD4 promoter duplication 120bp		long	TDT P-value=0.918, OR=1.04, 95% CI=0.70-1.56 TDT P-value=0.918, OR=1.04, 95% CI=0.70-1.56	no evidence	Non-significant
DRD4 promoter -521C/T	G/A		TDT P-value=0.166, OR=1.25, 95% CI=0.96-1.77 TDT P-value=0.166, OR=1.25, 95% CI=0.96-1.77	insignificant excess of allele A	Non-significant
DRD4 promoter -616C/G	C/G		TDT P-value=0.008, OR=1.63, 95% CI=1.16-2.38 TDT P-value=0.008, OR=1.63, 95% CI=1.16-2.38	significant over transmission	Significant
DRD4 promoter -376C/T	C/T		TDT P-value=0.572, OR=1.33, 95% CI=0.63-2.82 TDT P-value=0.572, OR=1.33, 95% CI=0.63-2.82	No distortion in the transmission	Non-significant

Genes reported by this study (count: 1)