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	Bobb AJ, 200515717291
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

Detail Info

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.
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 TrueAllele^TM PCR Premix,and 1 ul of [5uM] pooled DAT1, DRD5, and SNAP-25 primers. A thermal cycler heated plates at 50^oC for 5 min; 35 cycles of 95^oC for 15 sec, 65^oC for 30 sec, and 72^oC for 30 sec; and 72^oC for 15 min. Next, 5 ul of the PCR product, 0.26 ul of GeneScan^TM 500-LIZ^TM 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.

SNPs reported by this study (count: 16)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
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

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			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

Genes reported by this study (count: 12)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
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