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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	Langley K, 200918563476
Citation	Langley K., Fowler T. A., Grady D. L., Moyzis R. K., Holmans P. A., van den Bree M. B., Owen M. J., O'Donovan M. C. and Thapar A. (2009) "Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder." Eur Child Adolesc Psychiatry, 18(1): 26-32.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	151 cases and at least 442 control samples
Predominant Ethnicity	Caucasian
Population	United Kingdom
Age Group	Children/Adolescents : mean age 14.5 years (SD=1.7)

Detail Info

Summary	Utilizing a longitudinally assessed sample, they investigated the contribution of susceptibility gene variants, previously implicated through pooled or meta-analyses, to the developmental course of Attention-Deficit Hyperactivity Disorder over time. 151 children (aged 6-12) who met diagnostic criteria for ADHD were assessed using research diagnostic interviews during childhood and 5 years later in adolescence. Severity was defined as total number of ADHD symptoms at baseline and reassessment. Association with variants at DRD4, DRD5, and the dopamine transporter gene, DAT was analyzed using linear regression. As expected, affected individuals showed a decline in ADHD severity over time. The DRD4 48 bp VNTR 7-repeat and DRD5 CA(n) microsatellite marker 148 bp risk alleles were associated with persistent ADHD. Those possessing the DRD4 7 repeat risk allele showed less of a decline in severity at reassessment than those without the risk allele. Those carrying the DRD4 7 risk allele showed greater symptom severity at follow-up and less ADHD reduction over time. These findings support the hypothesis that some susceptibility genes for ADHD also influence its developmental course.
Total Sample	375 ADHD children were involved in the original cross-sectional studies, but 198 individuals were eligible, of them, 190 were traced and 151 completed all components of reassessment. Control data, previously utilised in studies of these gene variants were available from the United Kingdom Blood Transfusion Service and General Practice Registers. No additional demographic or clinical information, was available. For DRD4 data from 442 controls were available, for DRD5 data from 97 controls and for DAT1, there were data for 295 controls.
Sample Collection	British Caucasian
Diagnosis Description	Children with suspected or diagnosed ADHD, were originally recruited as part of a genetic study. Child and Adolescent Psychiatrists and Paediatricians in the Greater Manchester, South Wales and Avon areas of the United Kingdom referred children to the study. The children underwent an extensive assessment, including research diagnostic interviews. Individuals were excluded if they had a full scale IQ below 70, Tourette's syndrome, Pervasive Developmental Disorder or any Neurological disorder including Epilepsy. The sample for this longitudinal study was drawn from an original cross-sectional study that included 375 children who met DSM-III-R/DSM-IV criteria for ADHD or ICD-10 criteria for Hyperkinetic Disorder at baseline. This current paper focuses on a new longitudinal study of ADHD that included children from the original study who had reached adolescence. Five years later, those individuals aged 12 years or over were invited to participate in a follow up study. Of 198 individuals eligible, 190 were traced and 151 completed all components of reassessment (76% of those eligible).
Technique	DNA was extracted by phenol chlorophorm extraction from venous blood or buccal mouthwash samples. Genotyping of each of these markers has been described in previous publications and was blind to phenotypic status with respect to the measures presented in this paper. Briefly, genotyping of the DAT1 480 bp VNTR was performed using primers and conditions described by Daly and colleagues as detailed in Holmes and colleagues. The DRD5 CA(n) microsatellite marker was genotyped on an ABI 3100 capillary sequencer according to the primers and conditions described by Sherrington and colleagues. For the DRD4 48 bp VNTR, primer sets and analyses described previously were used. For some samples, adjacent SNPs known to be in strong linkage disequilibrium with the DRD4 7R VNTR were analyzed to confirm the genotype.
Analysis Method	For analysis of change in ADHD severity over time, linear regression analysis was performed with risk genotype as the independent variable and total number of DSM-IV ADHD symptoms at reassessment as the dependent variable, controlling for total number of DSM-IV ADHD symptoms at baseline. Where univariate analyses were found to be significant, analyses were repeated controlling for the significant covariates of age, sex, current DSM-IV conduct disorder symptoms and medication. All independent variables, including ADHD symptoms at baseline and follow up, as well as all linear covariates were normally distributed. Allele frequencies for those with baseline ADHD (all individuals) and persistent cases were compared to those for controls using analysis of 2x2 contingency tables. Individuals were classified as being at risk for a certain risk variant if they possessed; one or more DRD4 48 bp VNTR 7-repeat allele; one or more DRD5 (CA)n microsatellite 148 bp marker; and two copies of the DAT1 480 bp VNTR 10-repeat allele.
Result Description	Case-control analysis revealed significant association between the DRD4 48 bp VNTR 7-repeat allele and persistent ADHD. Similarly, the 148 bp risk allele of the DRD5 CA(n) microsatellite marker also significantly predicted baseline persistent ADHD diagnosis. The DAT1 variant was not associated with persistent ADHD or baseline ADHD.

Other variant reported by this study (count: 3)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
DRD5 5'-flanking (CT/GT/GA)n			Case-control analysis: P-value=0.02, OR=1.62 (95%CI: 1.06-2....... Case-control analysis: P-value=0.02, OR=1.62 (95%CI: 1.06-2.47) for baseline ADHD; P-value=0.02, OR=1.75, (95%CI=1.11-2.77) for persistent ADHD More...	significantly predicted baseline persistent ADHD diagnosis	Significant
SLC6A3 3'-UTR VNTR			Case-control analysis: P-value=0.61 for baseline ADHD; P-val...... Case-control analysis: P-value=0.61 for baseline ADHD; P-value=0.54 for persistent ADHD. More...	not associated with persistent ADHD or baseline ADHD	Non-significant
DRD4 exon3 VNTR			Case-control analysis: P-value=0.001, OR=1.86 (95%CI=1.30-2....... Case-control analysis: P-value=0.001, OR=1.86 (95%CI=1.30-2.65) for baseline ADHD; P-value=0.0001, OR=2.12 (95%CI=1.45-3.11) for persistent ADHD. More...	significant association between the DRD4 48 bp VNTR 7-repeat allele and 'persistent ADHD'.	Significant

Genes reported by this study (count: 3)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
SLC6A3	SLC6A3 480 bp VNTR is not associated with persistent ADHD or...... SLC6A3 480 bp VNTR is not associated with persistent ADHD or baseline ADHD. More...	Non-significant
DRD5	DRD5 CA(n) microsatellite significantly predicted baseline p...... DRD5 CA(n) microsatellite significantly predicted baseline persistent ADHD diagnosis . More...	Significant
DRD4	significant association between the DRD4 48 bp VNTR 7-repeat...... significant association between the DRD4 48 bp VNTR 7-repeat allele and 'persistent ADHD'. More...	Significant