Study Report
Basic Info
Reference |
Hawi Z, 200111443526
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Citation |
Hawi Z., Foley D., Kirley A., McCarron M., Fitzgerald M. and Gill M. (2001) "Dopa decarboxylase gene polymorphisms and attention deficit hyperactivity disorder (ADHD): no evidence for association in the Irish population." Mol Psychiatry, 6(4): 420-4.
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Study Design |
family-based |
Study Type |
Candidate-gene association study |
Sample Size |
85 families |
Predominant Ethnicity |
Caucasian |
Population |
Ireland |
Gender |
85% male |
Age Group |
Children/Adolescents
:
4-14 years
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Detail Info
Summary |
In this study, the 4-bp insertion/deletion variant mapped to the first neuronally expressed exon 1 at the dopa decarboxylase gene and two microsatellite markers flanking the gene were investigated for possible association with ADHD. Using HHRR, they observed an increased transmission (though not significant) of the 4-bp insertion (allele 1) to ADHD cases. However marginally significant excess transmission of allele 10 (213 bp) of the 39 microsatellite D7S2422 (~0.75 cM distal to dopa decarboxylase gene) was found. Interestingly, a haplotype containing both alleles is transmitted more frequently. Analysing data by the sex of transmitting parent showed a greater relative risk for paternal transmission of the 4-bp insertion allele and allele 10 of the D7S2422. This provides preliminary evidence that this locus or a closely mapped DNA variant may be involved in the genetic susceptibility to ADHD. |
Total Sample |
Twenty-one families consisted of mother and affected child, and 64 families consisted of mother, father and affected child (trios). The age range of the probands was between 4 and 14 years, with males accounting for 85%. The families were ethnically Irish with the exception of one family in which the father was Croatian. |
Sample Collection |
ADHD cases and available parents were recruited from child psychiatric clinics and schools in west County Dublin and from the Hyperactive and Attention Deficit Children's Support Group of Ireland. |
Diagnosis Description |
Details of diagnosis and clinical criteria can be found in Daly et al. Consensus diagnoses were made according to DSM-IV ADHD or UADD either with or without comorbidity. These diagnoses were based on all available clinical information and the Child Behaviour Checklist (CBCL), the Conners Parents and Teachers Rating Scales, and the Comprehensive Teachers Rating Scale (ACTeRS). The 25-item Wender-Utah Rating Scale (WURS) was applied to all parents. Familiality was defined as the presence of one or more parents with a score on the WURS of >36 (96% sensitive and specific for a retrospective diagnosis of childhood ADHD. |
Technique |
DNA was extracted from EDTA blood using the standard phenol chloroform procedure. The PCR primer sequences and conditions used to amplify the 4-bp insertion/deletion at the untranslated exon 1 of dopa were those used in Speight et al. Genotyping was achieved by incorporating palpha in the PCR mix and separating the product on 6% denaturing polyacrylamide gels. Two microsatellite markers (D7S2561 and D7S2422) flanking the dopa decarboxylase gene at the 5' and 3' ends were also genotyped using the semi-automated florescent methods on an ABI 377 DNA sequencer. |
Analysis Method |
They used the haplotype based haplotype relative risk (HHRR) design to avoid any potential population stratification. The chi-square test and Fisher's exact P were used to assess the significance of the transmission of alleles from parents to their affected children. All chi-square tests and P-values are presented without correction for multiple testing. They also used the programme TRANSMIT to examine haplotypes that might be transmitted more frequently to the ADHD cases. |
Result Description |
Using HHRR, they observed an increased transmission (though not significant) of the 4-bp insertion (allele 1) to ADHD cases (x2=2.72, P=0.1, RR=1.25). However marginally significant excess transmission of allele 10 (213 bp) of the 3' microsatellite D7S2422 (~0.75 cM distal to dopa decarboxylase gene) was found (x2=4.2, P=0.04, RR=1.48). Interestingly, a haplotype containing both alleles is transmitted more frequently (x2=5, P=0.025). Analysing data by the sex of transmitting parent showed a greater relative risk for paternal transmission of the 4-bp insertion allele and allele 10 of the D7S2422 (RR=1.48 and 1.63 respectively). |
Other variant reported by this study (count: 3)
Variant Name |
Allele Change |
Risk Allele |
Statistical Values |
Author Comments |
Result of Statistical Analysis |
DDC exon1 ins/del 4bp |
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Allele 1 (insertion) |
HHRR P-value=0.1, X2=2.72, RR=1.25 in the total s......
HHRR P-value=0.1, X2=2.72, RR=1.25 in the total sample
More...
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HHRR analyses did not attain statistical significance in the total sample but showed a greater relative risk for paternal transmission |
Non-significant
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DDC 3'-flanking D7S2422 |
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Allele 10 (213bp) |
HHRR P-value=0.04, X2=4.2, RR=1.48 in the total s......
HHRR P-value=0.04, X2=4.2, RR=1.48 in the total sample
More...
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the analysis showed increased transmission of allele 10 of the marker D7S2422 and showed a greater relative risk for paternal transmission |
Significant
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DDC 5'-flanking D7S2561 |
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Allele 3 (214bp) |
HHRR P-value=0.23, X2=1.43, RR=1.25 in the total ......
HHRR P-value=0.23, X2=1.43, RR=1.25 in the total sample
More...
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HHRR analyses did not attain statistical significance in the total sample |
Non-significant
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Genes reported by this study (count: 1)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
DDC |
haplotype containing allele 1 of the dopa gene and allele 10......
haplotype containing allele 1 of the dopa gene and allele 10 of D7S2422, TRANSMIT P-value=0.025, X2=5; the result showed a significant association with ADHD
More...
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Significant
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