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Large-scale studies
- Genome-wide Association Studies of ADHD
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- Meta-analysis Studies of ADHD
Data Summary
Study Report
Reference | Bobb AJ, 200515717291 |
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Citation | Bobb A. J., Addington A. M., Sidransky E., Gornick M. C., Lerch J. P., Greenstein D. K., Clasen L. S., Sharp W. S., Inoff-Germain G., Wavrant-De Vrieze F., Arcos-Burgos M., Straub R. E., Hardy J. A., Castellanos F. X. and Rapoport J. L. (2005) "Support for association between ADHD and two candidate genes: NET1 and DRD1." Am J Med Genet B Neuropsychiatr Genet, 134B(1): 67-72. |
Study Design | case-control and family-based |
Study Type | Candidate-gene association study |
Sample Size | 163 ADHD probands and 192 parents; 129 healthy controls |
Predominant Ethnicity | Caucasian |
Population | USA |
Gender | 53% male probands, 57% male controls |
Age Group | Children/Adolescents : mean age: 9.02, SD=2.22 years for probands, mean age: 15.99, SD=8.13 years for healthy controls |
Summary | DNA from 163 ADHD probands, 192 parents, and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes (5-HT1B, 5- HT2A, 5-HT2C, ADRA2A, CHRNA4, COMT, DAT1, DRD1, DRD4, DRD5, NET1, and SNAP-25). Analyses included case-control and family-based methods, and dimensional measures of behavior, cognition, and anatomic brain magnetic resonance imaging (MRI). Of the 12 genes examined, two showed a significant association with ADHD. Transmission disequilibrium test (TDT) analysis revealed significant association of two NET1 single nucleotide polymorphisms (SNPs) with ADHD; case-control analysis revealed significant association of two DRD1 SNPs with ADHD. No behavioral, cognitive, or brain MRI volume measurement significantly differed across NET1 or DRD1 genotypes at an alpha of 0.01. This study provides support for an association between ADHD and polymorphisms in both NET1 and DRD1; polymorphisms in ten other candidate genes were not associated with ADHD. |
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Total Sample | Children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defined ADHD were recruited locally and nationally. Fifty-three percent of the probands were male, and most were Caucasian (75% Caucasian, 12% African USAn, 10% Hispanic, 2% Asian, and 1% other); their average age was 9.02 (SD=2.22) years. A total of 163 ADHD probands and 192 parents were included in the analysis. They also recruited healthy controls locally and nationally. Of 129 controls, 57% were male, and most were Caucasian (75% Caucasian, 15% African USAn, 4% Hispanic, 3% Asian, and 2% other); their average age was 15.99 (SD=8.13) years. |
Sample Collection | Children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [USAn Psychiatric Association, 1994] defined ADHD were recruited locally and nationally. They also recruited healthy controls locally and nationally. |
Diagnosis Description | Children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defined ADHD were recruited locally and nationally. Psychiatric diagnoses were based on the Diagnostic Interview for Children and Adolescents (DICA)-Child, Adolescent, and Parent versions, revised. Other measures included the Conners Parent and Teacher Rating Scales, Child Behavior Checklist, Teacher Report Form, Full Scale Wechsler Intelligence Scale for Children, Third Edition (WISC-III), a computerized response inhibition task, and an anatomic brain MRI scan (see Castellanos et al., 2002 for details). The majority (94%) of probands were diagnosed with ADHD combined type, while 6% were diagnosed with primarily inattentive type. |
Technique | Single nucleotide polymorphism (SNP) genotyping with genomic DNA extracted from immortalized lymphoblastoid cell lines was performed using standard methods (see Gornick et al., 2004 for details). Microsatellite and variable number of tandem repeat (VNTR) polymorphism reactions were performed in a 384-well format in a total volume of 15 ul, with 5 ul of [2 ng/ul] genomic DNA, 9 ul of TrueAlleleTM PCR Premix,and 1 ul of [5uM] pooled DAT1, DRD5, and SNAP-25 primers. A thermal cycler heated plates at 50oC for 5 min; 35 cycles of 95oC for 15 sec, 65oC for 30 sec, and 72oC for 30 sec; and 72oC for 15 min. Next, 5 ul of the PCR product, 0.26 ul of GeneScanTM 500-LIZTM size standard, and 7.74 ul of formamidewere transferred to 96-well plates, which were placed in the ABI PRISM 3100-Avant Genetic Analyzer. Plates were analyzed using GENOTYPER software. |
Analysis Method | They used the phase known transmission disequilibrium test (TDT), where counts of allele transmissions from heterozygous parents at each SNP locus were analyzed with the TDTPHASE program version 2.37 [Dudbridge, 2003]. They also used the E-M algorithm in TDTPHASE for unknown phase haplotype estimation. The program COCAPHASE [Dudbridge, 2003] was used for case-control comparisons. QTPHASE [Dudbridge, 2003] was used for quantitative trait association analyses. |
Result Description | Of the 12 genes examined, two showed a significant association with ADHD. Transmission disequilibrium test (TDT) analysis revealed significant association of two NET1 single nucleotide polymorphisms (SNPs) with ADHD; case-control analysis revealed significant association of two DRD1 SNPs with ADHD. No behavioral, cognitive, or brain MRI volume measurement significantly differed across NET1 or DRD1 genotypes at an alpha of 0.01. This study provides support for an association between ADHD and polymorphisms in both NET1 and DRD1; polymorphisms in ten other candidate genes were not associated with ADHD. |
SNP | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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rs1800544 | allelic TDT P-value=0.05, OR=1.41 in case-control analysis; allelic TDT P-value=0.37, RR=1.26 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6090384 | allelic TDT P-value=0.47, OR=1.23 in case-control analysis; allelic TDT P-value=0.83, RR=1.1 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs2273505 | allelic TDT P-value=0.71, OR=1.12 in case-control analysis; allelic TDT P-value=0.27, RR=1.63 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs2273506 | allelic TDT P-value=0.72, OR=1.12 in case-control analysis; allelic TDT P-value=0.27, RR=1.63 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6313 | allelic TDT P-value=0.82, OR=1.04 in case-control analysis; allelic TDT P-value=0.83, RR=1.05 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6311 | allelic TDT P-value=0.96, OR=1.01 in case-control analysis; allelic TDT P-value=0.67, RR=0.91 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6314 | allelic TDT P-value=0.49, OR=1.19 in case-control analysis; allelic TDT P-value=0.3, RR=0.64 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6318 | allelic TDT P-value=0.65, OR=1.03 in case-control analysis; allelic TDT P-value=0.62, RR=1.29 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs4680 | allelic TDT P-value=0.27, OR=1.11 in case-control analysis; allelic TDT P-value=0.84, RR=1.04 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6347 | allelic TDT P-value=0.17, OR=1.22 in case-control analysis; allelic TDT P-value=0.27, RR=0.73 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs3785157 | allelic TDT P-value=0.87, OR=1.03 in case-control analysis; allelic TDT P-value=0.002, RR=2.28 in family-based analysis | there was preferential transmission of the T allele to ADHD ...... there was preferential transmission of the T allele to ADHD probands More... | Significant | ||
rs998424 | allelic TDT P-value=0.91, OR=0.98 in case-control analysis; allelic TDT P-value=0.009, RR=1.96 in family-based analysis | there was preferential transmission of the C allele to ADHD ...... there was preferential transmission of the C allele to ADHD probands More... | Significant | ||
rs6298 | allelic TDT P-value=0.18, OR=1.29 in case-control analysis; allelic TDT P-value=0.27, RR=1.41 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs6296 | allelic TDT P-value=0.22, OR=1.06 in case-control analysis; allelic TDT P-value=0.49, RR=1.21 in family-based analysis | non-significant association non-significant association | Non-significant | ||
rs265981 | allelic TDT P-value=0.008, OR=1.61 in case-control analysis; allelic TDT P-value=0.27, RR=1.31 in family-based analysis | ADHD probands were more likely than controls to have the A a...... ADHD probands were more likely than controls to have the A allele More... | Significant | ||
rs4532 | allelic TDT P-value=0.006, OR=1.63 in case-control analysis; allelic TDT P-value=0.4, RR=1.23 in family-based analysis | ADHD probands were more likely than controls to have the C a...... ADHD probands were more likely than controls to have the C allele More... | Significant |
Variant Name | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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DRD5 5'-flanking (CT/GT/GA)n | allelic TDT P-value=0.91, OR=0.93 in case-control analysis; ...... allelic TDT P-value=0.91, OR=0.93 in case-control analysis; allelic TDT P-value=0.89 in family-based analysis More... | non-significant association | Non-significant | ||
SLC6A3 exon15 VNTR | allelic TDT P-value=0.47, OR=1.12 in case-control analysis; ...... allelic TDT P-value=0.47, OR=1.12 in case-control analysis; allelic TDT P-value=0.16 in family-based analysis More... | non-significant association | Non-significant | ||
SNAP25 5'-UTR (ATTT)n | allelic TDT P-value=0.88, OR=0.99 in case-control analysis; ...... allelic TDT P-value=0.88, OR=0.99 in case-control analysis; allelic TDT P-value=0.31 in family-based analysis More... | non-significant association | Non-significant |
Gene | Statistical Values/Author Comments | Result of Statistical Analysis |
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SLC6A2 | revealed significant association of two SNPs with ADHD revealed significant association of two SNPs with ADHD | Significant |
CHRNA4 | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
SLC6A3 | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
ADRA2A | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
COMT | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
HTR2A | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
DRD5 | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
HTR2C | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
HTR1B | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
SNAP25 | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
DRD1 | revealed significant association of two SNPs with ADHD revealed significant association of two SNPs with ADHD | Significant |
DRD4 | no polymorphism was associated with ADHD no polymorphism was associated with ADHD | Non-significant |
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Last update: Feb 26, 2014