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	Halleland H, 200918802928
Citation	Halleland H., Lundervold A. J., Halmoy A., Haavik J. and Johansson S. (2009) "Association between catechol O-methyltransferase (COMT) haplotypes and severity of hyperactivity symptoms in adults." Am J Med Genet B Neuropsychiatr Genet, 150B(3): 403-10.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	435 cases and 383 controls
Predominant Ethnicity	Caucasian
Population	Norway
Gender	53.3% males in the ADHD group and 41.4% males in the control group
Age Group	Adults : >18 years, mean age 34.4 years (SD=10.5) in the ADHD group and 27.8 years (SD=6.7) in the control group

Detail Info

Summary	They hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val¹⁵⁸Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269. Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in their sample. The results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, they suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.
Total Sample	435 patients, and 383 ethnically matchedcomparison cases (138 students and 245 randomly selected persons
Sample Collection	The participants in the present study were recruited from all parts of Norway [Johansson et al., 2007].
Diagnosis Description	Most of them were originally referred by their primary physician to psychiatric out-patient clinics where they were diagnosed by psychiatrists or clinical psychologists. About 6% were diagnosed at psychiatric hospitals. The patients received the ADHD diagnosis as adults (82.3%) or during childhood (17.7%). However, all the participants were also officially diagnosed as having persistent ADHD as adults. The criteria used for diagnosing ADHD followed the national guidelines from the Norwegian regional ADHD expert committees; the ICD-10 research criteria. Those are compatible with the DSM-IV criteria. Some hyperactive, impulsive or inattentive symptoms that cause impairment should have been present before 7 years of age, and must be present in two or more settings [USAn Psychiatric Association, 2000]. Information about subtype of diagnosis was not collected in this study. There were no formal exclusion criteria.
Technique	ASRS was used to determine the levels of ADHD symptoms during the past six months. Medication status and symptoms were recorded at the time of patient inclusion. A conservative approach was chosen where every patientwithout confirmed information about medication at the time of scoring on the ASRS is categorized as nonmedicated. SNPs were selected to tag all three common putative functional haplotypes as described inNackley et al. [2006]. DNA was extracted either from whole blood, or from saliva using the OrageneTM DNA Self-Collection Kit from DNAGenotek(DNAGenotek, Inc., Ontario, Canada) at theHUNT biobank (Levanger, Norway). DNA from cases and controls were mixed on 96-well plates with a minimum of two internal controls and two blank samples on each plate. Genotyping of SNPs rs4680 and rs4818 was performed using the MassARRAYR iPLEXTM System (SEQUENOM, Inc., San Diego, CA) and the TaqMan allelic discrimination assay was used for SNPs rs6269 and rs4633. Total genotyping concordance rate was 100%.
Analysis Method	SPSS version 14.0.2 was used for one-way ANOVA and chi-square test tocompare age and gender between the groups. One-way ANOVA was used to explore if group status and medication were related to difference in scores on ASRS. Allele frequencies and single marker tests for each marker were calculated using the PLINK software. For the quantitative analysis (ASRS total score, hyperactivity/impulsivity score and inattention score), they performed linear regression both with the PLINK and SPSS 14.0.2 software, using gender, ADHD and current medication as cofactors. No significant deviations from Hardy-Weinberg equilibrium were detected for any marker. Haplotype analyses were performed using the WHAP and PLINK software with the same covariates as described above (similar results were obtained with conditional logistic regression as implemented by the UNPHASED software ). P- values are presented without correction for multiple testing.
Result Description	All four SNPs were in strong pair wise linkage disequilibrium (LD) with almost perfect correlation (r²>0.98) between rs6269-rs4818 and rs4633-rs4680. Only three common haplotypes were detected in the Norwegian sample. None of the four tested SNPs showed an association with ADHD as a categorical, dependent variable. However, all four SNPs showed tendency for association with the hyperactivity/impulsivity dimension of the ASRS. Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in their sample . The results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously.

SNPs reported by this study (count: 4)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs6269	G/A		Single marker test: P-value=0.62 (OR=1.05 [0.86-1.29]); Quantitative linear regression analysis: P-value=0.007 (beta=0.83) for hyperactivity subscale; P-value=0.61 (beta=-0.15) for inattention subscale; P-value=0.21 (beta=0.68) for ASRS total	no association with ADHD, but strongest association with hyp...... no association with ADHD, but strongest association with hyperactivity/impulsivity. More...	Significant
rs4818	G/C		Single marker test: P-value=0.42 (OR=1.09 [0.89-1.33]); Quantitative linear regression analysis: P-value=0.02 (beta=0.73) for hyperactivity subscale; P-value=0.34 (beta=-0.29) for inattention subscale; P-value=0.42 (beta=0.44) for ASRS total	no association with ADHD, but tendenial association with hyp...... no association with ADHD, but tendenial association with hyperactivity/impulsivity. More...	Significant
rs4680	G/A		Single marker test: P-value=0.62 (OR=1.05 [0.86-1.28]); Quantitative linear regression analysis: P-value=0.1 (beta=0.47) for hyperactivity subscale; P-value=0.10 (beta=-0.46) for inattention subscale; P-value=0.99 (beta=0.00) for ASRS total	no association with ADHD, but tendenial association with hyp...... no association with ADHD, but tendenial association with hyperactivity/impulsivity. More...	Non-significant
rs4633	C//T		Single marker test: P-value=0.66 (OR=1.05 [0.86-1.27]) \| Quantitative linear regression analysis: P-value=0.06 (beta=0.55) for hyperactivity subscale; P-value=0.30 (beta=-0.30) for inattention subscale; P-value=0.65 (beta=0.24) for ASRS total	no association with ADHD, but tendenial association with hyp...... no association with ADHD, but tendenial association with hyperactivity/impulsivity. More...	Non-significant

Genes reported by this study (count: 1)