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	Oades RD, 200818937842
Citation	Oades R. D., Lasky-Su J., Christiansen H., Faraone S. V., Sonuga-Barke E. J., Banaschewski T., Chen W., Anney R. J., Buitelaar J. K., Ebstein R. P., Franke B., Gill M., Miranda A., Roeyers H., Rothenberger A., Sergeant J. A., Steinhausen H. C., Taylor E. A., Thompson M. and Asherson P. (2008) "The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis." Behav Brain Funct, 4: 48.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	1180 offspring from 607 families
Predominant Ethnicity	Caucasian
Population	Belgium, Germany, Ireland, Israel, Spain, Switzerland, the Netherlands, United Kingdom
Gender	male 793 (67.2%); female 387 (32.8%)
Age Group	Children/Adolescents : 5-17 years

Detail Info

Summary	Here they demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC). Their sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. They then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach. In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant and aggressive behavioral impulsivity with a DRD4 variant are also described.
Total Sample	In this sample, 1180 offspring from 607 families had the necessary genotype and phenotype data to be included in the analysis. These individuals were recruited from 12 specialist clinics in 8 European countries (Belgium, Germany, Ireland, Israel, Spain, Switzerland, the Netherlands and the United Kingdom). The sample was aged 5-17 years on entry to the study.
Sample Collection	European Caucasian
Diagnosis Description	These individuals were recruited from 12 specialist clinics in 8 European countries (Belgium, Germany, Ireland, Israel, Spain, Switzerland, the Netherlands and the United Kingdom). these families were included in the study because they either 1) met the criteria for inattentive or hyperactive-impulsive ADHD or 2) were just below the threshold for meeting the ADHD-ct criteria. Diagnoses of ADHD-ct were based on the semistructured Parental Account of Children's Symptoms. For more details, please refer to the original publication.
Technique	14 genes with 582 single nucleotide polymorphisms (SNPs) were selected from the data available from the IMAGE study for the core analysis reported here. Blood samples were sent to Rutgers University Cell and DNA repository, New Jersey, U.S.A., where DNA was extracted. Genotyping was by simple sequence analysis on agarose gel, as described previously (details in the original publication). Data cleaning procedures were performed previously on the entire IMAGE set of SNP data and have been described.
Analysis Method	Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.
Result Description	In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.

SNPs reported by this study (count: 17)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs3758653			P-value=0.008178; FDR P-value=0.08178 for behavioral impulsivity	attained nominal significance for an association with impuls...... attained nominal significance for an association with impulsive behavioral aggression More...	Significant
rs3782025			P-value=0.026497; FDR P-value=0.20125 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs6561333			P-value=0.012237; FDR P-value=0.12237 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs6582071			P-value=0.010714; FDR P-value=0.10714 for behavioral impulsivity	attained nominal significance for an association with impuls...... attained nominal significance for an association with impulsive behavioral aggression More...	Significant
rs686			P-value=0.006978; FDR P-value=0.06978 in additive model for cognitive impulsivity; P-value=0.023762; FDR P-value=0.11881 in dominant model for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs7103411			P-value=0.021263; FDR P-value=0.10746 for behavioral impulsivity	attained nominal significance for an association with impuls...... attained nominal significance for an association with impulsive behavioral aggression More...	Significant
rs13189021			P-value=0.018997; FDR P-value=0.18997 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs10879352			P-value=0.015048; FDR P-value=0.06598 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs10767664			P-value=0.021492; FDR P-value=0.10746 for behavioral impulsivity	attained nominal significance for an association with impuls...... attained nominal significance for an association with impulsive behavioral aggression More...	Significant
rs2934966			P-value=0.027007; FDR P-value=0.10349 for behavioral impulsivity	attained nominal significance for an association with impuls...... attained nominal significance for an association with impulsive behavioral aggression More...	Significant
rs200173			P-value=0.003818; FDR P-value=0.00936 in additive model for cognitive impulsivity; P-value=0.00468; FDR P-value=0.00936 in dominant model	attained gene-wide statistical significance following an FDR...... attained gene-wide statistical significance following an FDR correction for multiple testing More...	Significant
rs1923886			P-value=0.033097; FDR P-value=0.16548 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs1672717			P-value=0.040249; FDR P-value=0.20125 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs1487275			P-value=0.019794; FDR P-value=0.06598 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs1406946			P-value=0.03163; FDR P-value=0.26692 for behavioral impulsivity; P-value=0.034898; FDR P-value=0.38387 for cognitive impulsivity	attained nominal significance for an association with impuls...... attained nominal significance for an association with impulsive behavioral aggression and cognitive impulsivity More...	Significant
rs1352250			P-value=0.011413; FDR P-value=0.06598 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant
rs13306221			P-value=0.042211; FDR P-value=0.22758 for cognitive impulsivity	attained nominal significance for an association with cognit...... attained nominal significance for an association with cognitive impulsivity More...	Significant

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A4 intron2 VNTR			P-value= 0.050 for cognitive impulsivity P-value= 0.050 for cognitive impulsivity	nominally significant association	Significant
DRD4 exon3 VNTR			P-value= 0.014 for impulsive aggressive behavior P-value= 0.014 for impulsive aggressive behavior	nominally significant association	Significant

Genes reported by this study (count: 10)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
DRD1	1 SNP showed significant association 1 SNP showed significant association	Significant
PNMT	2 SNPs showed significant association 2 SNPs showed significant association	Significant
HTR1E	1 SNP showed significant association 1 SNP showed significant association	Significant
DRD4	1 SNP and 1 polymorphism showed significant association 1 SNP and 1 polymorphism showed significant association	Significant
BDNF	3 SNPs showed significant association 3 SNPs showed significant association	Significant
HTR3B	2 SNPs showed significant association 2 SNPs showed significant association	Significant
TPH2	4 SNPs showed significant association 4 SNPs showed significant association	Significant
HTR2A	2 SNPs showed significant association 2 SNPs showed significant association	Significant
SLC6A4	1 polymorphism showed significant association 1 polymorphism showed significant association	Significant
SLC6A3	1 SNP showed significant association 1 SNP showed significant association	Significant