Study Report
Basic Info
Reference |
Mill J, 2004 (a)14755441
|
Citation |
Mill J., Curran S., Richards S., Taylor E. and Asherson P. (2004) "Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD." Am J Med Genet B Neuropsychiatr Genet, 125B(1): 38-42.
|
Study Design |
family-based |
Study Type |
Candidate-gene association study |
Sample Size |
188 probands |
Predominant Ethnicity |
Caucasian |
Population |
United Kingdom |
Age Group |
Children/Adolescents
|
Detail Info
Summary |
A microsatellite located near the dopamine D5 receptor (DRD5) gene has been associated with ADHD in a number of studies, but other polymorphisms within the vicinity of this gene have not been examined. In this study they genotyped three microsatellites spanning the DRD5 region in a large clinical sample. Overall, little evidence was found to support a role for DRD5 in ADHD. No evidence of association with either the previously associated DRD5 marker, or a repeat in the promoter region of the gene were found. However, significant association for an allele of D4S615, a dinucleotide repeat located 131 kb 3' of DRD5 that has been previously associated with schizophrenia was found. A global test incorporating all alleles of this marker, however, was not significant and thus this finding needs replication before any conclusions can be made. |
Total Sample |
In total, DNA from 188 probands and their families were used for this study. DNA was available from both parents for 121 of the families, and from only the mother in 64 families. The 113 of the affected families had at least 1 sibling who was also genotyped. Out of 188 cases included in this study, 176 had the combined subtype, 8 had the hyperactive/impulsive subtype and 4 the inattentive subtype. |
Diagnosis Description |
Cases were referred for assessment if they were thought by experienced clinicians to have a diagnosis of the combined subtype of ADHD under DSM-IV criteria, with no significant Axis I comorbidity apart from oppositional defiant disorder (ODD) and conduct disorder (CD). Parents of referred cases were interviewed with a modified version of the child and adolescent psychiatric assessment (CAPA). Information on ADHD symptoms at school were obtained using the long form of the Conners questionnaire. Following assessments HYPESCHEME data sheets were completed using data gathered from the research interview, questionnaire and where necessary review of case notes. HYPESCHEME diagnoses were checked against researcher applied DSM-IV criteria and discrepancies reviewed by two researchers. Where consensus could not be reached, cases were brought to case conference and final consensus agreement made with a senior clinical researcher. All the subjects used in this study had an IQ above 70, were free of neurological disease and damage, and did not have any congenital disorders known to cause hyperactivity. Cases were included in this study if they had a diagnosis of ADHD under DSM-IV criteria. |
Technique |
DNA was obtained using buccal swabs and extracted as described in Freeman et al. [2003]. Three polymorphisms were genotyped by PCR. Fluorescently-tagged products for each of the markers were separated on an ABI 3100 Genetic Analyzer (PE Applied Biosystems, Foster City, CA) and analysed using GENOTYPER (PE Applied Biosystems) software. |
Analysis Method |
Family genotype data was analysed using David Clayton's program TRANSMIT (v5.4). TRANSMIT tests for association between genetic markers and disease by examining the transmission of markers from parents to affected offspring. Data from unaffected siblings (or siblings whose disease status is unknown) may be used to narrow down the range of possible parental genotypes that need to be considered, thus maximising the power of current sample to detect an association with any of the DRD5 markers tested. The levels of linkage disequilibrium (LD) between the markers were investigated. LD relationships were assessed in the parental samples using the program 2LD, written by Jing Hua Zhao. Two standardised measures of LD were calculated-D' and phi 2. |
Result Description |
DRD5 (CT/GT/GA)n Microsatellite: No overall evidence for biased transmission of any of the alleles of this polymorphismto individuals with ADHD was found. DRD5 Promoter Dinucleotide: there was no significant evidence of biased transmission of any of the alleles of this marker to ADHD probands. D4S615: Overall there was no evidence to suggest this marker is associated with ADHD. However, some evidence for biased under-transmission of allele 6 (244 bp) to ADHD probands (allele-specific P=0.01) was found suggesting that this may be a protective allele. |
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 |
|
148bp |
TRANSMIT multi-locus P-value=0.63, single locus P-value=0.69......
TRANSMIT multi-locus P-value=0.63, single locus P-value=0.69 for allele 148bp
More...
|
no overall evidence for biased transmission |
Non-significant
|
DRD5 3'-flanking D4S615 |
|
244bp |
TRANSMIT multi-locus P-value=0.16, single locus P-value=0.01......
TRANSMIT multi-locus P-value=0.16, single locus P-value=0.01 for allele 244bp
More...
|
Overall there was no evidence to suggest this marker is associated with ADHD, but some evidence for biased under-transmission of allele 244bp was found. |
Significant
|
DRD5 upstream (TC)n |
|
|
TRANSMIT multi-locus P-value=0.40
TRANSMIT multi-locus P-value=0.40
|
no significant evidence of biased transmission |
Non-significant
|
Genes reported by this study (count: 1)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
DRD5 |
significant association for an allele of D4S615 was found, b......
significant association for an allele of D4S615 was found, but a global test incorporating all alleles of this marker was not significant.
More...
|
Significant
|